+publisher:"Penn State University" +contributor:("Robert G Levenson, Committee Member")

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Penn State University

1. Kuzu, Omer Faruk. Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents .

Degree: 2014, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/23545

► According to American Cancer Society’s 2014 Cancer Facts report, cancer is the second leading cause of death in United States and over half million people… (more)

▼ According to American Cancer Society’s 2014 Cancer Facts report, cancer is the second leading cause of death in United States and over half million people are expected to die from this deadly disease. Until 2030, it is forecasted to be the primary cause of death with a 45 % increase in new cancer cases. Skin cancer is the most common form of cancer in the United States with more than 3 million cases is diagnosed, annually. Most skin cancers can be surgically removed when detected early. However, melanoma, the malignancy of pigment producing skin cells, is the most aggressive and dangerous of all skin cancers. It accounts for approximately 80% of skin cancer associated deaths. Until 2013, dacarbazine (DTIC), an alkylating chemotherapeutic agent that was approved by U.S. Food and Drug Administration (FDA) in 1975, was the most common drug used for the treatment of melanoma. Recently, targeted agents such as those targeting the MAP kinase pathway have been approved by the FDA for the treatment of melanoma. However, in nearly all cases, development of drug resistance limits the efficacy of these agents to only few months. Therefore, there is need for development of new melanoma therapeutics that have long term efficacy. Recently, we have identified Leelamine, a small natural compound as a potential chemotherapeutic agent against melanoma. Leelamine was 3 to 5 fold more effective at inhibiting viability of malignant melanoma cell lines compared to other skin cells. More importantly, leelamine showed efficacy in-vivo leading to ~60% decrease in the growth of xenografted melanoma tumors. However, very few reports were available regarding the mechanism of action of this agent. Therefore, the primary objective of my dissertation is to identify the molecular mechanisms leading to leelamine-mediated cancer cell death. Our studies suggested that as a weakly basic amine, leelamine displayed lysosomotropism that lead to its accumulation inside the acidic organelles and consequently disrupted cholesterol egress from lysosomes. Inhibition of intracellular cholesterol transport by leelamine was the leading cause of cell death. These findings led to the development of our secondary objective, which was to explore the chemotherapeutic efficacy of other potential cholesterol transport inhibitors. A class of weakly basic lysosomotropic compounds called Functional Inhibitors of Acid Sphingomyelinases (FIASMA) were identified as potential cholesterol transport inhibitors and shown to be effective against melanoma cells as well as xenografted melanoma tumors. In this dissertation, we show that as a cholesterol transport inhibitor, leelamine and several FIASMA compounds disrupt autophagic flux and inhibit receptor-mediated endocytosis resulting in the shutdown of key pathways to which melanoma cells are addicted. Inhibition of lysosomotropic accumulation of compounds by Bafilomycin-A1 co-treatment or depletion of cellular cholesterol with β-cyclodextrin co-treatment was able to attenuate the cell death mediated by these… Advisors/Committee Members: Gavin Peter Robertson, Dissertation Advisor/Co-Advisor, Robert G Levenson, Committee Member, Jin Ming Yang, Committee Member, Sinisa Dovat, Committee Member.

Subjects/Keywords: Melanoma; tricyclic antidepressant; antipsychotic; FIASMA; lysosomotropic; intracellular cholesterol transport inhibitor

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APA (6^th Edition):

Kuzu, O. F. (2014). Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/23545

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kuzu, Omer Faruk. “Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents .” 2014. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/23545.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kuzu, Omer Faruk. “Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents .” 2014. Web. 01 Mar 2021.

Vancouver:

Kuzu OF. Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents . [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/23545.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kuzu OF. Lysosomotropic Cholesterol Transport Inhibitors as Potential Chemotherapeutic Agents . [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/23545

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. Imperio, Caesar Gerald. From behavior to epigenetics: Individual differences in heroin addiction.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/26303

► Heroin addiction is a disease of chronic relapse that harms the individual through the devaluation of natural rewards in favor of finding and using drugs.… (more)

▼ Heroin addiction is a disease of chronic relapse that harms the individual through the devaluation of natural rewards in favor of finding and using drugs. Although destructive, studies have shown that approximately 50% of the human population will transition from controlled heroin use to addiction. Given the variability, there is a need to determine why certain individuals respond differently to heroin. Therefore the goal of this dissertation is to determine at the behavioral and molecular levels why individual differences in addiction-like behavior occur with heroin. In Chapter 2, I developed an animal model that used avoidance of a heroin-paired saccharin cue to stratify rats on their addiction-like behaviors. Greater avoidance of the reward cue was linked with greater drug taking, drug loading, drug escalation, and increased relapse-like behaviors. Using next generation sequencing in Chapter 3, avoidance of the drug-paired taste cue was linked to individual differences in gene expression in the nucleus accumbens. In Chapter 4, I used taste reactivity to assess the perceived hedonic value of the natural reward cue as it came to predict the opportunity to self-administer heroin. Previous cocaine studies have shown that intraoral administration of a drug-paired taste cue elicits negative taste reactivity (gaping) and greater gaping is correlated with greater drug taking behaviors. The results show that, unlike cocaine, intraoral delivery of a heroin-paired taste cue does not support either robust or sustained aversive taste reactivity behavior. Lastly, given the profound effect the environment has on the development of addiction, environmental enrichment was employed to determine if persistent enrichment status can attenuate the development of addiction-like behavior (Chapter 5). Enrichment was shown to attenuate the motivation to work for heroin and prevent drug-seeking behaviors following a period of drug abstinence. Enrichment also buffered the effects of heroin exposure on mRNA expression in the brain. Furthermore, changes in neural DNA methylation were found due to heroin exposure and enrichment status. Taken together, the data presented in this thesis demonstrate the dynamic interplay between an individual’s genetic background and the environment on the development and expression of opiate addiction and associated epigenetic mediators. Advisors/Committee Members: Patricia Sue Grigson Kennedy, Dissertation Advisor/Co-Advisor, Scott C Bunce, Committee Member, Willard M Freeman, Special Member, Robert G Levenson, Committee Member, Victor J Ruiz Velasco, Committee Member.

Subjects/Keywords: Addiction; Heroin; Reward; Epigenetics; Enrichment; RNA-seq

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APA (6^th Edition):

Imperio, C. G. (2015). From behavior to epigenetics: Individual differences in heroin addiction. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/26303

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Imperio, Caesar Gerald. “From behavior to epigenetics: Individual differences in heroin addiction.” 2015. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/26303.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Imperio, Caesar Gerald. “From behavior to epigenetics: Individual differences in heroin addiction.” 2015. Web. 01 Mar 2021.

Vancouver:

Imperio CG. From behavior to epigenetics: Individual differences in heroin addiction. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/26303.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Imperio CG. From behavior to epigenetics: Individual differences in heroin addiction. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/26303

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Huber-keener, Kathryn Joyce. Alterations In Gene Expression As A Response of Tumor Cells To Stresses .

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/15352

► Cancer cells are constantly under stress, a factor which needs to be taken into consideration during the treatment of cancers. Both intrinsic and extrinsic stresses… (more)

▼ Cancer cells are constantly under stress, a factor which needs to be taken into consideration during the treatment of cancers. Both intrinsic and extrinsic stresses impact the development and progression of neoplasms, down to the level of individual proteins and genes. Stresses like nutrient deficiency, hypoxia, and the immune response are present during normal tumor growth and throughout treatment. Tumor cells that survive these stresses are more adept at surviving hostile conditions and are more resistant to current therapies. Stress, therefore, shapes the tumor cell population. Gene expression alterations are the driving feature behind the adaptive ability of cancer cells to these stresses, and therefore, careful examination of these gene expression changes must be undertaken in order to develop effective therapies. In the present investigations, we first explore the global alterations of gene expression in tamoxifen resistance. Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam-resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERα functions, cell cycle regulation, gen expression, and mitochondrial modification. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and a protein called SIRT3 in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent. After such a global exploration of cancer cell responses to stress, we next investigated a mechanism of cancer cell survival by exploring the alterations in protein synthesis inhibitor eEF-2K. Studies show that eEF-2K plays a role in cell survival through this inhibition of protein synthesis and that its protein levels are increased in cancer. Post-translational modification of translation machinery is important for its regulation and could be critical for survival of cancer cells encountering stress. Thus, the purpose of our study is to examine the regulation of eEF-2K during stress with a focus on the phosphorylation status and stability of EF-2K protein in cancer cells. Using two human glioma cell lines (T98G and LN229), under stress conditions, we found a paradoxical increase in eEF-2K protein expression with a decrease in eEF-2K protein stability. Phosphorylation may play a role in this altered protein stability as EF-2K has multiple phosphorylation sites that are phosphorylated by the… Advisors/Committee Members: Jin Ming Yang, Dissertation Advisor/Co-Advisor, Robert G Levenson, Committee Member, Rongling Wu, Committee Member, Willard Freeman, Committee Member, Andrea Manni, Committee Member.

Subjects/Keywords: eEF-2K; tamoxifen; glioma; breast cancer; protein synthesis; next generation-sequencing; protein stability

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Huber-keener, K. J. (2013). Alterations In Gene Expression As A Response of Tumor Cells To Stresses . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15352

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Huber-keener, Kathryn Joyce. “Alterations In Gene Expression As A Response of Tumor Cells To Stresses .” 2013. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/15352.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Huber-keener, Kathryn Joyce. “Alterations In Gene Expression As A Response of Tumor Cells To Stresses .” 2013. Web. 01 Mar 2021.

Vancouver:

Huber-keener KJ. Alterations In Gene Expression As A Response of Tumor Cells To Stresses . [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/15352.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Huber-keener KJ. Alterations In Gene Expression As A Response of Tumor Cells To Stresses . [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/15352

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. Pritchett, Carolyn Elisabeth. Glucagon-like eptide-1 mediates hedonic intake and food reward.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/17443

► Current theories on the cause and prevention of obesity highlight the importance of the reward system in feeding, food choices, and hyperphagia. Palatable foods, commonly… (more)

▼ Current theories on the cause and prevention of obesity highlight the importance of the reward system in feeding, food choices, and hyperphagia. Palatable foods, commonly high in fat and sugar content, can engage the reward system and increase motivation to procure and consume such foods, independent of caloric need or nutritional value. Excessive consumption of highly palatable foods is believed to be a key environmental factor in obesity rates. Of major concern are the complex and long-lasting changes to various neural systems following obesity. Among these include changes to mesolimbic dopamine signaling along the central reward pathway; altered dopamine signaling has been linked with both a genetic predisposition for obesity and dietary induced obesity. Recently, more attention has been given to alterations in the gut-brain system that occur with obesity, such as notable differences in the incretin hormone glucagon-like-peptide-1 (GLP-1). Interestingly, obesity-induced GLP-1 deficits appear to be reversed following Roux-en-Y gastric bypass surgery, and changes to GLP-1 and similar peptides have been theorized as critical factors in the success of this surgical procedure. While GLP-1 has been clearly defined as both an incretin and a satiety hormone, less is known about the influence of GLP-1 on systems driving hedonic intake and food reward. Furthermore, the debate continues as to the role of GLP-1 in obesity, and its precise impact in Roux-en-Y gastric bypass surgery. To investigate the role of GLP-1 on the dopamine reward system, and how GLP-1 is influenced in obesity, we investigated how temporarily altering the dopamine and GLP-1 systems of lean and dietary induced obese (DIO) rats influenced hedonic intake of palatable solutions using the synthetic GLP-1 agonist Exendin-4 and receptor specific dopamine antagonists. Peripherally administered dopamine antagonists led to significant reductions in the intake of palatable carbohydrates, with notable differences between the two dietary obese groups despite similar body weight gain; one group was fed a high fat-high energy diet and one fed a fat-carbohydrate high energy combination diet. Furthermore, these differences were dependent upon the receptor subtype targeted, with D1 receptor antagonism producing more potent reductions than D2 receptor antagonism, and upon the type of carbohydrate, with sucrose intake more susceptible to dopamine antagonism than fructose intake. These data indicate dopamine signals do change in obesity, and the type of diet leading to obesity can influence the extent and perhaps nature of such changes. This data implies that differential responses may occur to different palatable foods, and indicates why individuals may respond to different treatment regimens with various success rates. Using an identical animal model of two DIO groups, we again compared responses to sucrose and fructose in chow-fed lean and DIO rats after activation of the GLP-1 receptor by the synthetic analog Exendin-4. Exendin-4 (ip) reduced both sucrose and… Advisors/Committee Members: Andras Hajnal, Dissertation Advisor/Co-Advisor, Andras Hajnal, Committee Chair/Co-Chair, Ralph Norgren, Committee Member, Robert G Levenson, Committee Member, Christopher J Lynch, Committee Member, Kirsteen Nairn Browning, Committee Member.

Subjects/Keywords: GLP-1; reward; dopamine; obesity; high fat diets; hedonic; food intake; mesolimbic

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pritchett, C. E. (2013). Glucagon-like eptide-1 mediates hedonic intake and food reward. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/17443

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pritchett, Carolyn Elisabeth. “Glucagon-like eptide-1 mediates hedonic intake and food reward.” 2013. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/17443.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pritchett, Carolyn Elisabeth. “Glucagon-like eptide-1 mediates hedonic intake and food reward.” 2013. Web. 01 Mar 2021.

Vancouver:

Pritchett CE. Glucagon-like eptide-1 mediates hedonic intake and food reward. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/17443.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pritchett CE. Glucagon-like eptide-1 mediates hedonic intake and food reward. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/17443

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

5. Stahl, Edward L. MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS .

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12394

► This dissertation is the result of a detailed investigation into the effects of the antiarrhythmic drug amiodarone on muscarinic receptors. We have found that amiodarone… (more)

▼ This dissertation is the result of a detailed investigation into the effects of the antiarrhythmic drug amiodarone on muscarinic receptors. We have found that amiodarone interacts with muscarinic receptors in a specifically allosteric manner. In radioligand binding studies, amiodarone was only able to partially inhibit the binding of the orthosteric antagonist [3H]N-methylscopolamine (NMS). Additionally, amiodarone was able to alter the rate of dissociation of [3H]NMS from M1, M2, and M5 receptors. These findings suggest that NMS and amiodarone are able to bind to the receptor simultaneously. Furthermore, the pharmacology of the effect on NMS dissociation demonstrated that amiodarone does not interact with the “common” site at which gallamine, obidoxime, and many other muscarinic allosteric ligands are known to bind. In functional studies, amiodarone enhanced the response stimulated by an acetylcholine concentration that produced about 20% of maximal arachidonic acid release from the M5 receptor. However, under the same conditions, amiodarone did not enhance M1 arachidonic acid release. More detailed studies at M5 found that the effect of amiodarone was to enhance the efficacy of acetylcholine, without increasing its potency. This was the first demonstration of allosteric enhancement of efficacy at the M5 receptor, and the first demonstration of enhancement of efficacy but not potency at any muscarinic receptor. Amiodarone also enhanced the maximal level of agonist-stimulated release of arachidonic acid (AA) by the M3 muscarinic receptor; this enhancement was observed for acetylcholine and for the partial agonist pilocarpine. A similar effect of amiodarone was observed when pilocarpine was used to stimulate inositol phosphate (IP) metabolism, but not when acetylcholine was used. Subsequent studies showed that the IP response exhibited a much larger receptor reserve than the AA response, and reduction of that reserve by receptor alkylation unmasked amiodarone’s enhancement of the maximal IP response to acetylcholine. Modulating the receptor reserve also revealed acetylcholine’s greater affinity (KA) for the conformation of the receptor that mediates the AA response. The amiodarone analog Nethylamiodarone (NEA) did not alter the maximal agonist response stimulated by M3, but merely reduced agonist potency (that is, it appeared to be an antagonist). However, the action of NEA could be clearly distinguished from the action of the orthosteric antagonist NMS. Demonstration of this point was facilitated by an elaboration of Hall’s allosteric two-state model; this new model represents a system composed of two ligands that compete with each other at the orthosteric site and two ligands that compete with each other at the allosteric site. In conclusion, amiodarone competes with NEA at a novel, extracellular, allosteric site to enhance the maximal stimulation evoked by acetylcholine and pilocarpine in two different responses. Advisors/Committee Members: John Ellis, Dissertation Advisor/Co-Advisor, John Ellis, Committee Chair/Co-Chair, Victor Alan Canfield, Committee Member, Robert G Levenson, Committee Member, Blaise Peterson, Committee Member.

Subjects/Keywords: G protein-coupled receptors; acetylcholine; muscarinic; allosteric; amiodarone

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Stahl, E. L. (2012). MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12394

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Stahl, Edward L. “MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS .” 2012. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/12394.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Stahl, Edward L. “MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS .” 2012. Web. 01 Mar 2021.

Vancouver:

Stahl EL. MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS . [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/12394.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Stahl EL. MECHANISTIC STUDIES OF THE ALLOSTERIC MODULATION OF MUSCARINIC RECEPTORS . [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/12394

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

6. Yuill, Matthew Buchanan. FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN.

Degree: 2017, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/14505mby116

► The goal of this study was to test the hypothesis that the Cannabinoid 2 Receptor (CB2R) functionally interacts with the opioid system to modulate inflammatory… (more)

▼ The goal of this study was to test the hypothesis that the Cannabinoid 2 Receptor (CB2R) functionally interacts with the opioid system to modulate inflammatory pain. Additionally, we tested mechanisms mediating tolerance to multiple opioids, and to the prototypical cannabinoid Δ9-THC. CB2R agonists produce low levels of side effects and no tolerance relative to other opioid and cannabinoid agonists, making them an attractive pharmacotherapeutic target. This study assessed the anti-nociceptive effects of a selective CB2R agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with the activity of opioids in this model. JWH-133 produces dose-dependent anti-nociception during both the acute pain and inflammatory pain phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. The efficacy of JWH-133 was blocked by application of a CB2R selective antagonist (SR144528). After eleven once-daily injections of 1 mg/kg JWH-133, no tolerance was observed in the formalin test. Conversely, wild-type mice become tolerant to Δ9-THC, morphine, and fentanyl within eleven days. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant CB2R and Mu opioid receptor (MOR) interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine. Similar results were found for cross-tolerance between JWH-133 and fentanyl, suggesting opioid and CB2R cross-tolerance is unidirectional in this model. However, preliminary data suggests co-administration of JWH-133 with morphine modestly attenuates morphine tolerance in the formalin model. Furthermore, isobolographic analysis revealed that co-administration of a fixed-ratio combination of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that CB2R may functionally interact with MOR to modulate anti-nociception and tolerance in inflammatory pain, which suggests clinical utility. Advisors/Committee Members: Daniel James Morgan, Dissertation Advisor/Co-Advisor, Patricia Sue Grigson-Kennedy, Committee Chair/Co-Chair, Robert G Levenson, Committee Member, John Ellis, Committee Member, Jossee Guindon, Outside Member.

Subjects/Keywords: CB2R; morphine; pain; tolerance; formalin; JWH-133; opioid; cannabinoid agonist

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yuill, M. B. (2017). FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/14505mby116

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Yuill, Matthew Buchanan. “FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN.” 2017. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/14505mby116.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Yuill, Matthew Buchanan. “FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN.” 2017. Web. 01 Mar 2021.

Vancouver:

Yuill MB. FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN. [Internet] [Thesis]. Penn State University; 2017. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/14505mby116.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Yuill MB. FUNCTIONAL INTERACTIONS BETWEEN OPIOIDS AND A CANNABINOID RECEPTOR 2 AGONIST IN INFLAMMATORY PAIN. [Thesis]. Penn State University; 2017. Available from: https://submit-etda.libraries.psu.edu/catalog/14505mby116

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

7. Erickson-Ridout, Kathryn Kelly. METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12194

► Second-generation antipsychotics (SGA) are a widely prescribed class of drugs (1, 2) for the management of many disorders including schizophrenia, bipolar disorder, and treatment-resistant depression.… (more)

▼ Second-generation antipsychotics (SGA) are a widely prescribed class of drugs (1, 2) for the management of many disorders including schizophrenia, bipolar disorder, and treatment-resistant depression. The number of SGAs on the pharmaceutical market and their popularity has increased as clinical trials showed higher rates of responders, better functional capacity, an improved quality of life, and fewer extrapyramidal symptoms (EPS) and prolactin elevation side effects compared to first-generation antipsychotics (FGA). SGAs are recommended as the first-line treatment for schizophrenia and treatment resistant depression (3, 4). Nevertheless, SGAs are associated with numerous adverse effects, most notably marked weight gain leading to obesity, metabolic syndrome, type II diabetes, dyslipidemia, and heart disease (5). Compared to the general population, SGA adverse effects shorten patient life-span by an estimated 25 years (6) primarily due to cardiovascular disease (CVD), increased medication non-adherence and clinical burden, costing billions of dollars in healthcare annually (7-9). The most severe weight gain phenotypes occur with the SGAs clozapine (CLZ) and olanzapine (OLZ). Thus, it is important to identify mechanisms that underlie SGA adverse effects and develop interventions to prevent SGA-associated weight gain. Pharmacogenetics is the study of how genetic variation affects pharmacokinetics and pharmacodynamics, thereby influencing the efficacy and tolerability of a drug (10-12). The goal of pharmacogenetic studies is to identify genetic targets that predict the most efficacious drug and dose for a given individual, or reveal an individual’s risk of treatment failure or adverse effects before starting a specific treatment, thus providing “personalized medicine.” SGA pharmacogenetic studies and individualized medicine are vital to improving outcomes using currently available SGAs and to designing more efficacious treatments in psychiatric medicine. Treatment effectiveness trials show that most SGAs work in a subset of patients and, in other patients, either lack efficacy or cause debilitating metabolic adverse effects that discourage patient adherence to treatment (13-16). It is not clear which pharmacogenetic targets, if any, predispose an individual to treatment efficacy or failure with SGAs. However, plasma concentrations of SGAs reflect brain concentrations of the drugs and have been correlated to SGA response , risk of weight gain and other adverse effects (17-22). Interindividual plasma concentrations are not necessarily predicted by the dose administered (17), suggesting that genetic variability in genes coding for drug metabolizing enzymes (DMEs) could affect SGA efficacy and tolerability (19). DMEs are classified as Phase I or Phase II depending on the type of reaction they catalyze. The uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) are one group of Phase II enzymes that mediate greater than one-third of Phase II drug metabolism (23) and influence the plasma levels and clearance of a given… Advisors/Committee Members: Philip Lazarus, Dissertation Advisor/Co-Advisor, Philip Lazarus, Committee Chair/Co-Chair, Robert G Levenson, Committee Member, Elliot Saul Vesell, Committee Member, Robert Gabbay, Committee Member.

Subjects/Keywords: drug metabolism; antipsychotics; UDP-glucuronosyltransferases; olanzapine; pharmacogenetics; clozapine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Erickson-Ridout, K. K. (2011). METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12194

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Erickson-Ridout, Kathryn Kelly. “METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES .” 2011. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/12194.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Erickson-Ridout, Kathryn Kelly. “METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES .” 2011. Web. 01 Mar 2021.

Vancouver:

Erickson-Ridout KK. METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/12194.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Erickson-Ridout KK. METABOLISM OF SECOND-GENERATION ANTIPSYCHOTICS BY URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASES . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12194

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

8. Bourbon, Nicole A. Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/5843

► Ceramide, a sphingomyelin-derived second messenger, has been shown to stimulate signaling pathways that lead to growth arrest, differentiation or apoptosis. However, the mechanisms by which… (more)

▼ Ceramide, a sphingomyelin-derived second messenger, has been shown to stimulate signaling pathways that lead to growth arrest, differentiation or apoptosis. However, the mechanisms by which ceramide induces these cellular phenotypes are unclear at this time. Our studies establish a new paradigm for actions of lipid-derived second messengers: coordinating assembly of multi-factoral signaling complexes. The Stress-Activated Protein Kinase (SAPK) pathway has been implicated in cell growth arrest and/or apoptosis. In addition, studies have linked ceramide with activation of the SAPK cascade. However, the mechanism by which ceramide leads to activation of this cascade is unclear at this time. Our studies demonstrate that ceramide activates the SAPK cascade via direct activation of Protein Kinase C zeta (PKCz) in human embryonic kidney cells (HEK 293). Upon activation by ceramide, PKCz forms a signaling complex with upstream components of the SAPK cascade, including MEKK1 and SEK1. These studies demonstrate a novel mechanism by which ceramide activates the SAPK pathway to induce cell cycle arrest. A parallel pathway to the SAPK cascade is the Extracellular signal-Regulated Kinase (ERK) cascade. We and others have shown that the inhibitory action of ceramide on cell growth involves inhibition of the ERK pathway. Therefore, we investigated the mechanism by which ceramide inhibits this pathway. Our studies demonstrate that ceramide inhibits PKC epsilon activity and subsequent interaction with upstream components of the ERK cascade. These studies characterize a mechanism by which ceramide induces growth arrest through inhibition of the ERK cascade. Another signaling pathway critical in cell survival and proliferation is the PI3K/Akt1 cascade. Recent studies have demonstrated that ceramide inhibits Akt1. However, the mechanism of Akt1 inhibition by ceramide is unclear. Therefore, we investigated the role of PKCz in ceramide-mediated inhibition of the Akt1 cascade. Our studies revealed that inhibition of Akt1 by ceramide is PKCz-dependent. Collectively, our studies demonstrate several complimentary mechanisms by which ceramide induces cell growth arrest. The ability of ceramide to induce growth arrest, without inducing significant apoptosis or necrosis, may be of therapeutic value in the prevention or control of cell proliferation during inflammatory renal and vascular diseases. Advisors/Committee Members: Steven S Levison, Committee Member, Mark Kester, Committee Chair/Co-Chair, Elliot Saul Vesell, Committee Member, Melvin Lee Billingsley, Committee Member, Robert G Levenson, Committee Member.

Subjects/Keywords: PKC; MAPK; Ceramide; SAPK; ERK; Signaling Complexes; Sphingolipids

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bourbon, N. A. (2008). Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/5843

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bourbon, Nicole A. “Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest .” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/5843.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bourbon, Nicole A. “Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest .” 2008. Web. 01 Mar 2021.

Vancouver:

Bourbon NA. Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/5843.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bourbon NA. Ceramide Differentially Regulates Protein Kinase C/ Mitogen Activated Protein Kinase Pathways: Implications for Growth Arrest . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/5843

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

9. Wickenheisser, Jessica K. Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6011

► Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women of reproductive age, and is characterized by infertility, hirsutism, abnormal follicular development,… (more)

▼ Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 5-10% of women of reproductive age, and is characterized by infertility, hirsutism, abnormal follicular development, and increased ovarian androgen production. The phenotype of elevated androgen production persists in theca cells isolated from PCOS women and maintained in long-term culture. Increased androgen biosynthesis in PCOS theca cells is correlated with increased enzyme activity and gene expression of several steroidogenic enzymes responsible for androgen biosynthesis including cytochrome P450 17a-hydroxylase (CYP17) and cytochrome P450 cholesterol side chain cleavage (CYP11A). The overall objective of this thesis research was to test the hypothesis that altered transcriptional activation of the CYP17 promoter contributes to increased CYP17 gene expression in PCOS. Specifically, the mechanism(s) involved in increased CYP17 expression was examined by I) comparison of CYP17 promoter activities in normal and PCOS theca cells, II) examination of minimal region(s) of the CYP17 promoter required for increased CYP17 gene expression, and III) identification of putative transcriptional regulators involved in CYP17 gene expression in normal and PCOS theca cells. Studies were also initiated to examine whether the transcriptions factors involved in increased CYP17 transcription in PCOS theca cells coordinately increase CYP11A gene expression. The comparison of CYP17 promoter function in normal and PCOS theca cells indicated that CYP17 transcription was increased in PCOS theca cells. Sequences within the general boundaries of -235 to -109 bp of the CYP17 promoter were required for increased promoter function in PCOS theca cells. Additional deletion and mutational analysis of the CYP17 promoter was performed to characterize basal and cAMP-response elements and identify the minimal sequences involved in increased CYP17 promoter function in PCOS. Results of these analyses demonstrated that sequences between -188 and -147 bp of the CYP17 promoter were required for significant basal promoter function, whereas, cAMP-dependent regulation was conferred by two separate regions located within -172/-140 bp and -109/-61 bp. Sequences between -188 and -140 bp were both necessary and sufficient for increased promoter function in PCOS theca cells. Scanning mutation analysis of this region demonstrated that a 16 bp sequence, between -174 and -158 bp, was required for increased promoter function in PCOS theca cells. Examination of this sequence revealed a nuclear factor-1 (NF-1) binding site within -174/-162 bp of the promoter. A specific NF-1 family member, NF-1C, was found to bind this sequence and repress CYP17 promoter function in theca cells. Mutation of this NF-1 site ablated NF-1C binding and NF-1C-dependent CYP17 repression. Comparison of NF-1C binding in normal and PCOS nuclear extracts demonstrated that the level of NF-1C binding was reduced in PCOS. CYP11A promoter function was also repressed by cotransfection of NF-1C in theca… Advisors/Committee Members: Janette Marie Mcallister, Committee Chair/Co-Chair, Patrick Quinn, Committee Member, Gary Alan Clawson, Committee Member, Richard Scott Legro, Committee Member, Robert G Levenson, Committee Member.

Subjects/Keywords: theca cells; ovary; transcription; CYP17; polycystic ovary syndrome

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wickenheisser, J. K. (2008). Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6011

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wickenheisser, Jessica K. “Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells.” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6011.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wickenheisser, Jessica K. “Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells.” 2008. Web. 01 Mar 2021.

Vancouver:

Wickenheisser JK. Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6011.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wickenheisser JK. Transcriptional Regulation of the 17alpha-Hydroxylase Gene in Normal and Polycystic Ovary Syndrome Ovarian Theca Cells. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6011

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

10. Yura, Renee E. MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8602

► Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in kidney and intestinal epithelial cells. They… (more)

▼ Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in kidney and intestinal epithelial cells. They are also expressed in the skin and in certain populations of leukocytes. Meprins have been implicated in several inflammatory diseases, such as renal ischemia, diabetic nephropathy, and inflammatory bowel disease, indicating a role for these enzymes in modulation of the immune response. Prior to the initiation of this work, extensive information about the structure and in vitro behavior of the meprins was known, but little was known about their in vivo roles in immune modulation. These studies are the first to demonstrate a relationship between the inflammatory response and the meprins in both systemic and bladder challenge models. The aim of this work was to determine the role of meprins in the host response to gram-negative uropathic Escherichia coli (E. coli). Initial studies demonstrated marked increases in meprin alpha expression in the urine of women with active urinary tract infections (UTIs), implicating meprin involvement in the host response to bacterial infections. To examine further the role of meprins in the host response to UTI, meprin alpha knockout (alphaKO) and wild-type (WT) mice were challenged with a transurethral inoculation of uropathic E. coli. In this localized model of inflammation, bladder myeloperoxidase (MPO) activity, bladder weight, and bladder permeability were significantly less in alphaKO compared to WT mice after induction of UTI. These data indicate that meprin A is pro-inflammatory, contributing to leukocyte infiltration, edema, and epithelial damage. To determine whether the action of meprin A was the result of a direct interaction with E. coli, extensive in vitro studies were carried out. Meprin A did not decrease the binding of E. coli to bladder cells in culture, nor did it degrade the pili that are responsible for the attachment of E. coli to the bladder epithelium. No evidence of direct interactions between meprin A and E. coli has been found, indicating that the differential response observed in meprin alphaKO mice in comparison to WT is indirect and likely involves the immune system. A large component of the immune response to E. coli is directed toward lipopolysaccharide (LPS) in the bacterial cell wall. Therefore, the responses of meprin alphaKO, meprin beta knockout (betaKO), meprin alphabeta double knockout (alphabetaKO), and WT mice after intraperitoneal (i.p.) LPS challenge were examined. Genotype-specific differences in response to LPS were observed as early as 1 h after challenge with 2.5 mg/kg i.p. E. coli LPS. Meprin alphaKO mice displayed a decreased systemic response to LPS compared to WT mice and meprin betaKO mice, as indicated by lower blood urea nitrogen (BUN) levels, lower serum TNFalpha levels, and less severe hypothermia, implicating meprin in modulation of the host immune response to endotoxin. These data are consistent with those from UTI studies,… Advisors/Committee Members: Judith S Bond, Committee Chair/Co-Chair, Sarah Bronson, Committee Member, Robert G Levenson, Committee Member, Andrea Manni, Committee Member, W. Brian Reeves, Committee Member.

Subjects/Keywords: meprins; metalloproteases; lipopolysaccharide; urinary tract infection; transgenic mouse models

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yura, R. E. (2008). MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8602

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Yura, Renee E. “MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI .” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/8602.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Yura, Renee E. “MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI .” 2008. Web. 01 Mar 2021.

Vancouver:

Yura RE. MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/8602.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Yura RE. MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8602

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

11. Pizoli, Carolyn Elizabeth. Abnormal Cerebellar Signaling Induces Dystonia in Mice.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6046

► Dystonia is a relatively common neurological syndrome characterized by twisting movements or sustained abnormal postures. The pathophysiology of dystonia remains poorly understood; however, recent evidence… (more)

▼ Dystonia is a relatively common neurological syndrome characterized by twisting movements or sustained abnormal postures. The pathophysiology of dystonia remains poorly understood; however, recent evidence suggests that abnormal cerebellar signaling contributes to the expression of dystonia. To study the role of the cerebellum in dystonia, we first analyzed neurotransmission in the cerebellum of the genetically dystonic mouse, tottering. A deficiency in excitatory but not inhibitory neurotransmission in tottering mice was seen after superfusion of cerebellar synaptosomes with 60mM KCl. Further analysis of the role of cerebellar Purkinje cells in the generation of tottering dystonia was completed through breeding a transgene responsible for post-developmental Purkinje cell death onto the tottering mouse. Prior to Purkinje cell degeneration, transgenic tottering mice exhibited classical tottering dystonic events; however, the same animals failed to exhibit dystonia after Purkinje cell loss had occurred in adulthood. The loss of the dystonic phenotype in double mutant mice indicates that Purkinje cells and the cerebellar cortex participate in the pathogenesis of dystonia in the tottering mouse. These data support the theory that an abnormal signal from the cerebellar cortex of tottering mice is responsible for the dystonic phenotype. To test this theory and examine the role of the cerebellum in dystonia, we developed a novel mouse model of dystonia. Microinjection of low-doses of the glutamate analogue kainic acid into the cerebellum of wild type mice elicited reliable and reproducible dystonia. Transgenic mice lacking Purkinje cells showed dramatically decreased dystonia after kainic acid injections, supporting the theory that aberrant cerebellar excitation is sufficient to produce dystonia. Together these data suggest that the cerebellum plays a role in the pathophysiology underlying dystonia. Advisors/Committee Members: Ellen J Hess, Committee Chair/Co-Chair, Melvin Lee Billingsley, Committee Chair/Co-Chair, Robert G Levenson, Committee Member, Teresa Wood, Committee Member, James Robert Connor, Committee Member.

Subjects/Keywords: dystonia; cerebellum; tottering; calcium channels; kainic acid

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pizoli, C. E. (2008). Abnormal Cerebellar Signaling Induces Dystonia in Mice. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6046

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pizoli, Carolyn Elizabeth. “Abnormal Cerebellar Signaling Induces Dystonia in Mice.” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6046.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pizoli, Carolyn Elizabeth. “Abnormal Cerebellar Signaling Induces Dystonia in Mice.” 2008. Web. 01 Mar 2021.

Vancouver:

Pizoli CE. Abnormal Cerebellar Signaling Induces Dystonia in Mice. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6046.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pizoli CE. Abnormal Cerebellar Signaling Induces Dystonia in Mice. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6046

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

12. Kalapila, Aley George. O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7914

► Bis-electrophiles are compounds that are capable of forming cross-links between two nucleophilic sites. This chemical attribute has contributed to increased genotoxicity of such compounds in… (more)

▼ Bis-electrophiles are compounds that are capable of forming cross-links between two nucleophilic sites. This chemical attribute has contributed to increased genotoxicity of such compounds in a variety of in vitro and in vivo biological test systems. Dibromoalkanes, which are one class of bis-electrophiles, are environmental toxic agents that have been used globally as pesticides, chemical intermediates and solvents in agriculture and industry. It has been shown that the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), paradoxically augments the mutagenicity and cytotoxicity of 1,2-dibromoethane (DBE) in Escherichia coli (E.coli). DBE reacts with AGT to generate a S-(2-bromoethyl) intermediate which forms a highly reactive half-mustard at the Cys145 alkyl acceptor site. Due to its DNA-binding ability, AGT can readily facilitate the reaction between DNA and the half-mustard thus causing the formation of DNA adducts. It is likely that in E. coli these covalent AGT-DNA adducts are the major factor mediating DBE-promoted genotoxicity. The studies described in this thesis have examined human alkyltransferase (hAGT)-mediated toxicity with other bis-electrophiles, specifically butadiene diepoxide (BDO) and epibromohydrin (EBH), which are epoxide compounds. In vitro studies were performed to investigate the reaction of hAGT with BDO and EBH. Covalent binding to DNA was observed when purified recombinant wild-type hAGT (wt-hAGT) was incubated with either BDO or EBH in the presence of an [35S]–labelled oligonucleotide. Unlike similar experiments with DBE, hAGT-DNA cross-link formation was also observed with both compounds when a mutant hAGT protein was used with its Cys145 active site residue altered to an alanine (C145A). This verified the ability of these epoxide compounds to cross-link at another residue on hAGT aside from its active site. Further analyses indicated the alternate cross-link site to be Cys150, a residue situated on the periphery of the repair protein active site pocket, in close proximity to the DNA binding motif of hAGT. Results obtained using gel electrophoresis assays led us to conclude that both BDO and EBH exhibit two different mechanisms for generating the AGT-DNA adducts. This adduct formation can occur via an initial reaction between both the protein and compound or between protein and DNA. Studies in hAGT-expressing E.coli and CHO cells have confirmed the potentiation of toxicity by BDO, EBH and the dibromoalkanes in both model systems. With EBH and BDO, the enhancement in genotoxicity was also observed in E.coli expressing the inactive C145A-hAGT mutant, albeit not to the same degree as seen with wt-hAGT. This AGT-mediated toxicity was eliminated following expression of a C145A/C150S-hAGT double mutant indicating that covalent DNA adduct formation at the Cys150 residue were likely responsible for the increased toxicity observed in E.coli expressing the C145A mutant. Investigation into the types of genomic alterations induced at the bacterial rpoB gene locus and the mammalian… Advisors/Committee Members: Anthony Edward Pegg, Committee Chair/Co-Chair, Kristin Ann Eckert, Committee Member, Philip Lazarus, Committee Member, Lisa M Shantz, Committee Member, Robert G Levenson, Committee Member.

Subjects/Keywords: dibromoalkanes; dibromomethane; dibromoethane; AGT; O6-alkylguanine-DNA alkyltransferase; DNA repair; Bis-electrophiles; butadiene diepoxide; epibromohydrin; epichlorohydrin; epoxides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kalapila, A. G. (2009). O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7914

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kalapila, Aley George. “O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS .” 2009. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/7914.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kalapila, Aley George. “O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS .” 2009. Web. 01 Mar 2021.

Vancouver:

Kalapila AG. O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/7914.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kalapila AG. O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE - MEDIATED TOXICITY OF BIS-ELECTROPHILES: BIOCHEMICAL MECHANISMS . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/7914

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

13. Lee, Brian D. Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6151

► Multidrug resistance (MDR) is a phenomenon by which tumor cells develop reduced sensitivity to anticancer drugs, which often leads to the failure of cancer chemotherapy.… (more)

▼ Multidrug resistance (MDR) is a phenomenon by which tumor cells develop reduced sensitivity to anticancer drugs, which often leads to the failure of cancer chemotherapy. A prominent mechanism of MDR is the overexpression of the multidrug efflux pump, P-glycoprotein (P-gp), which decreases the intracellular accumulation of many anticancer drugs leading to increased tumor growth. Intensive efforts are underway to develop clinically useful MDR modulators that inhibit the function of P-gp for use in combination with established anticancer drugs. To study the in vivo systemic effects of P-gp-specific inhibitors on reversing P-gp-mediated MDR, we developed a solid tumor model utilizing immunocompetent animals. Using in vitro cytotoxicity and drug accumulation assays, two transformed murine cell lines, JC and TIB-75, were found to demonstrate the P-gp-mediated MDR phenotype. In contrast, two similar lines did not express functional P-gp. Western blot analyses confirmed the expression of P-gp and the lack of expression of the closely related drug efflux protein MRP1 in the JC and TIB-75 cell lines. The JC cell line displayed excellent tumorgenicity and consistent growth kinetics when implanted into immunocompetent Balb/c mice. Animals treated with a combination of a known MDR modulator, cyclosporin A, and a cytotoxic drug, doxorubicin, exhibited significantly reduced tumor growth compared to untreated controls or animals treated with either cyclosporin A or doxorubicin alone. Therefore, this syngeneic solid tumor model provides a new in vivo system that can be used to evaluate the efficacy of P-gp inhibitors in an immunocompetent host and should provide improved prediction of the clinical utility of these compounds. In our search for improved MDR modulators, we identified a novel series of substituted pyrroloquinolines that selectively inhibits the function of P-gp without modulating multidrug resistance-related protein 1 (MRP1). These compounds were evaluated for their toxicity towards drug sensitive tumor cells (i.e. MCF-7, T24) and for their ability to antagonize P-gp-mediated drug resistant cells (i.e. NCI/ADR) and MRP1-mediated resistant cells (i.e. MCF-7/VP). The in vitro cytotoxicity and drug accumulation assays demonstrated that the dihydropyrroloquinoline analogs inhibit P-gp to varying degrees without any significant inhibition of MRP1. One of the analogs, PGP-4008, showed the highest level of P-gp inhibition (P-gp antagonism score ≈ 17) in vitro and was further evaluated in vivo. PGP-4008 inhibited tumor growth in the JC murine syngeneic P-gp-mediated MDR solid tumor model when given in combination with doxorubicin. The dose of PGP-4008 (100 mg/kg) and the route of administration (intraperitoneal) used in the tumor model resulted in rapid systemic absorption with plasma concentrations exceeding the in vitro effective dose (0.8 µg/ml) for 2 h after administration. PGP-4008 did not alter the plasma distribution of concomitantly administered anticancer drugs. Furthermore, signs of systemic… Advisors/Committee Members: Charles D Smith, Committee Chair/Co-Chair, Melvin Lee Billingsley, Committee Member, Robert G Levenson, Committee Member, Jong Kak Yun, Committee Member.

Subjects/Keywords: P-glycoprotein; multidrug resistance; in vivo tumor model; actinomycin D transport

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lee, B. D. (2008). Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6151

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lee, Brian D. “Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators.” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6151.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lee, Brian D. “Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators.” 2008. Web. 01 Mar 2021.

Vancouver:

Lee BD. Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6151.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lee BD. Development and Characterization of P-glycoprotein specific Multidrug Resistance Modulators. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6151

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

14. Quiterio, Shane Joseph. MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6143

► HIV-1-associated dementia (HAD), which arises as a consequence of HIV-1 infection of the central nervous system (CNS), may be initiated by events within the bone… (more)

▼ HIV-1-associated dementia (HAD), which arises as a consequence of HIV-1 infection of the central nervous system (CNS), may be initiated by events within the bone marrow and peripheral immune system that lead to HIV-1 infection and activation of monocytic cells or their progenitors. Cells of the monocyte/macrophage lineage, which play important roles in HIV-1-associated neuropathogenesis, arise from CD34+ hematopoietic progenitor cells (HPCs) within the bone marrow and peripheral blood. CD34+ HPCs in the bone marrow are generally resistant to HIV-1 infection, likely due to deficiencies in HIV-1 coreceptor expression. However, cells of the monocytic lineage that arise from these precursor cells are able to support a productive HIV-1 infection, indicating that the process of differentiation from CD34+ HPCs to monocytes or macrophages may induce changes in cell surface receptors and transcription factors that favor viral entry and productive replication. In studies of HIV-1 genomic sequence compartmentalization, gp160 sequences isolated from deep white matter of a HAD patient’s brain were more closely related to sequences isolated from bone marrow and monocytes within the blood, suggesting either similar paths of viral evolution or migration of HIV-1-infected cells from the bone marrow to the brain. The differentiation of HIV-1-infected bone marrow cells and their migration to the brain could represent an important step in the development of HIV-1-associated neuropathogenesis and HAD. The central hypothesis of this thesis is that differentiation of bone marrow CD34+ progenitor cells leads to increased HIV-1 susceptability, LTR activation, and virus production that promotes the alteration of signaling pathways associated with increased cellular trafficking. The TF-1 erythromyeloid CD34+ progenitor cell line has been used to model bone marrow progenitor cell differentiation and to examine HIV-1 coreceptor expression levels during phorbol myristate acetate (PMA)-induced differentiation. Reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analyses were used to measure the expression of TF-1 cell RNA and surface proteins that are either crucial for HIV-1 binding and entry or indicative of cellular differentiation. TF-1 cells express the HIV-1 receptor CD4 and very low or undetectable levels of the HIV-1 coreceptors CXCR4 and CCR5. However, TF-1 cells had increased expression of CXCR4 and CCR5 coreceptors after PMA treatment, with high expression levels of both coreceptors 48-72 hr post-treatment. Expression of the activation marker CD69 also increased dramatically within 24 hr after PMA treatment. These results indicate that during progenitor cell differentiation the cells may become more susceptible to HIV-1 infection as a consequence of increased levels of the chemokine receptors involved in HIV-1 binding and entry. Cellular differentiation of bone marrow-derived progenitor monocytic cells can produce a distinct array of transcription factors that can modulate the activity of the HIV-1… Advisors/Committee Members: Brian Wigdahl, Committee Chair/Co-Chair, Shao Cong Sun, Committee Member, Robert Harold Bonneau, Committee Member, Robert G Levenson, Committee Member, Andrew Thomas Henderson, Committee Member.

Subjects/Keywords: HIV-1; bone marrow; CNS; CD34; progenitor; differentiation; coreceptor; LTR; dementia; HAD

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Quiterio, S. J. (2008). MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6143

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Quiterio, Shane Joseph. “MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE.” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6143.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Quiterio, Shane Joseph. “MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE.” 2008. Web. 01 Mar 2021.

Vancouver:

Quiterio SJ. MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6143.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Quiterio SJ. MODELING HIV-1 INFECTION OF BONE MARROW PROGENITOR CELLS: IMPLICATIONS FOR HIV-1 CNS DISEASE. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6143

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

15. Luu, Kieu. Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6576

► Human O6-alkylguanine-DNA alkyltranserase (AGT) is a widely expressed DNA repair protein present in prokaryotes and eukaryotes. AGT repairs O6-alkylguanine adducts in DNA via a stoichiometric… (more)

▼ Human O6-alkylguanine-DNA alkyltranserase (AGT) is a widely expressed DNA repair protein present in prokaryotes and eukaryotes. AGT repairs O6-alkylguanine adducts in DNA via a stoichiometric reaction that transfers the alkyl group onto an internal cysteine residue of the protein. This irreversible reaction inactivates AGT and de novo protein synthesis is required to produce more active protein. AGT protects normal cells from the mutagenic and carcinogenic effects of alkylation, but overexpression of AGT by cancer cells confers resistant to chemotherapeutic agents. The development of AGT inhibitors may prove useful in enhancing cancer chemotherapy. O6-Benzylguanine (b6G) is a potent inactivator of AGT. We showed that a single-stranded (ss) 7-mer oligodeoxyribonucleotide (oligo) containing multiple b6G can inhibit AGT activity in vitro. The protein is more efficient at reacting with b6G residues positioned near the 5'-end compared to those positioned near the 3'-end. In vivo, oligos containing single or multiple b6G can also sensitize HT29 cells to killing by BCNU. The position of b6G in an oligo may confer some protection from serum nucleases as oligos with b6G near the 5'- or 3'-end tend to have a longer half-life. Studies done with 16-mer oligos containing O6-methylguanine (m6G) at different positions also showed a trend in which there is an increase in the ED50 values for AGT inactivation with methylated lesions located towards the extreme 3'-end of the oligo. The ED50 values for the 16-mers with m6G positioned at the second, sixth, and eleventh nucleotide from the 5'-end were between 9-13 nM for wild type AGT. However, the ED50 values for the 16-mers with m6G positioned at the fourteenth and fifteenth nucleotide from the 5'-end were 57 nM and >50 microM, respectively. AGT repaired adducts at all positions equally well in duplex 16-mer oligos except those at positions 2 and 15. These results suggest that AGT recognizes the polarity in DNA and requires a minimum of four nucleotides 3' of an m6G lesion in order to productively bind and efficiently repair that lesion. The preference for AGT to repair 5'-end lesions in short oligos suggested that AGT may bind DNA in an oriented manner and scans directionally (3' to 5') to identify and repair O6-alkylguanine lesions. Using a single-stranded 70-mer oligo with an m6G lesion near either end, we confirmed that AGT preferentially (3.5 fold) repaired the 5'-end m6G lesion than the 3'-end lesion. However, this preference was not apparent in double-stranded oligos. A streptavidin/biotin-dT block was inserted between the two m6G lesions in the 70-mer oligo to impede the action of AGT. Compared to the appropriate controls, a streptavidin/biotin-dT block proximal to the 5'-end m6G in a single-stranded oligo decreased the repair of that lesion by about 2.6 fold while the repair of the 3'-end m6G was unaffected. A block distal to the 5'-end m6G decreased the repair of the 5'-end m6G to a lesser extent (1.7 fold) than the proximal block, while the repair of the 3'-end m6G… Advisors/Committee Members: Anthony Edward Pegg, Committee Chair/Co-Chair, Kristin Ann Eckert, Committee Member, Robert G Levenson, Committee Member, Charles D Smith, Committee Member, Lisa M Shantz, Committee Member.

Subjects/Keywords: DNA repair; AGT; alkyltransferase; alkylation; chemotherapy resistance; O6-alkylguanine-DNA alkyltransferase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Luu, K. (2008). Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6576

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Luu, Kieu. “Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase.” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6576.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Luu, Kieu. “Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase.” 2008. Web. 01 Mar 2021.

Vancouver:

Luu K. Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6576.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Luu K. Positional and directional repair of O6-alkylguanine lesions by human O6-alkylguanine-DNA alkyltransferase. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6576

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

16. Fureman, Brandy Ellen. L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/5866

► Mutations in calcium channels cause episodic neurological disorders in humans and paroxysmal phenotypes in mice. Tottering mice display stress-induced attacks of a movement disorder due… (more)

▼ Mutations in calcium channels cause episodic neurological disorders in humans and paroxysmal phenotypes in mice. Tottering mice display stress-induced attacks of a movement disorder due to a P/Q-type calcium channel mutation and cerebellar L-type calcium channel upregulation.L-type calcium channels were assessed in studies of calcium uptake, radioligand binding and in situ hybridization in tottering mice. These studies confirmed the increase in tottering cerebellar L-type calcium channels. Mutant mice also exhibited unique responses to repeated exposure to an L-type calcium channel antagonist (nimodipine) and agonist (BAY K8644). These studies provide further evidence of L-type calcium channel misregulation in the tottering mouse cerebellum. In developing tottering mice, restraint stress did not produce motor attacks until twenty-two days of age; attack frequencies at p22 were similar to adults. A second phenotype, aberrant cerebellar tyrosine hydroxylase mRNA expression, was not detected until after the onset of stress-induced motor attacks. These studies more precisely define the temporal relationship between these phenotypes, suggesting that aberrant calcium-responsive gene expression is a consequence of the intense cerebellar activation associated with motor attacks. In adult tottering mice, attacks were reliably precipitated by stressful environmental disturbances, caffeine and alcohol administration; these agents are widely known triggers in human episodic disorders. Thus, tottering mice provide an excellent model to study common pathophysiological mechanisms underlying trigger phenomena in ion channelopathies. As activation of hormonal systems is a common feature of tottering mouse triggers, the influence of stress hormones on tottering mouse attacks was assessed. Glucocorticoids were neither necessary nor sufficient for the expression of this behavior; pharmacological blockade of the corticotropin-releasing hormone receptor type 1 (CRF-1) did not prevent stress-induced motor attacks. Potential therapeutics including ethosuximide, phenytoin and carbamazepine failed to prevent motor attacks. However, L-type calcium channel antagonist nimodipine prevented caffeine- and alcohol-induced attacks, and the glutamatergic antagonist MK-801 was effective in preventing attacks induced by restraint stress. The results of these studies suggest that abnormal ionic signaling triggered through calcium-dependent mechanisms in cerebellar networks produces periods of hyperexcitability in the tottering mouse brain. The unique neurocircuitry of the cerebellum may amplify these abnormal signals once they are produced. Advisors/Committee Members: Ellen J Hess, Committee Chair/Co-Chair, Theresa L Wood, Committee Member, Robert G Levenson, Committee Member, Robert J Milner, Committee Chair/Co-Chair, Melvin Lee Billingsley, Committee Member.

Subjects/Keywords: mutant mouse; tyrosine hydroxylase; nimodipine; dyskinesia; trigger; voltage-dependent calcium channel; development; BAY K8644; animal model; behavior; paroxysmal; movement disorder

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fureman, B. E. (2008). L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/5866

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fureman, Brandy Ellen. “L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders .” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/5866.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fureman, Brandy Ellen. “L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders .” 2008. Web. 01 Mar 2021.

Vancouver:

Fureman BE. L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/5866.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fureman BE. L-type calcium channel regulation in the P/Q-type calcium channel mutant mouse, tottering, a model for episodic neurological disorders . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/5866

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

17. De Cotiis, Daniel A. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9804

► Neuronal Calcium Sensor 1 (NCS-1) is an acidic, highly helical protein (MW 23 kDa), which is involved in a variety of cellular pathways including exocytosis… (more)

▼ Neuronal Calcium Sensor 1 (NCS-1) is an acidic, highly helical protein (MW 23 kDa), which is involved in a variety of cellular pathways including exocytosis and G-protein linked receptor desensitization. NCS-1 contains an N-terminal myristoylation modification, as well as three EF-hand domains which bind calcium with moderate to high affinity. These attributes have been previously shown to affect the structural and functional behavior of the protein. In order to better characterize these changes, a protocol presented here has been designed and optimized to produce large quantities of recombinant N-myristoylated and unmodified NCS-1 in E. coli. Using this technique, novel mutants showing a spectrum of functional deficiencies are expressed, isolated and then characterized by a number of assays. The large quantities of homogenous protein produced are shown to be suitable for biophysical studies using a variety of in vivo and in vitro techniques. Contrary to what would be expected for a protein of small size, NCS-1 interacts with a wide diversity of other proteins. One mechanism by which NCS-1 could assume this functional assortment of roles is by forming higher order homo-complexes. Experimental results presented here demonstrate that NCS-1 is capable of forming calcium dependent homo-dimer complexes. The propensity for self-association is enhanced by N-terminal myristoylation. In the absence of ligand, all three functional EF-hand sites must be intact in order for NCS-1 dimerization to occur. As NCS-1 plays a wide diversity of roles in the cell, the formation of homo-dimers may have pronounced functional implications. NCS-1 forms a signaling complex with the D2 dopamine receptor (D2R) and other downstream effectors, ultimately regulating desensitization of the receptor in response to dopamine signaling. As a result, this regulatory complex may be involved in a number of neurological disease states including schizophrenia and bipolar disorder. A better understanding of the biophysical and regulatory details of this complex will have important implication for understanding disease pathology and exploring novel drug treatments. Using a fluorescent peptide substrate in a fluorescence polarization assay, the equilibrium binding behavior of the NCS-1 / D2R interaction is described here. The formation of the NCS-1 / D2R complex is shown to be calcium dependent and involve the NCS-1 dimer. The contribution of the various EF-hand domains to binding is also investigated, and a discrete role in dimerization and binding is implied for each pair of EF-hand domains. The outcomes of these experiments could be used to optimize a large format drug screen scaled from this assay system, which could ultimately isolate lead compounds for the treatment of D2R related diseases. Advisors/Committee Members: John Michael Flanagan Jr., Dissertation Advisor/Co-Advisor, John Michael Flanagan Jr., Committee Chair/Co-Chair, Maria Christine Bewley, Committee Member, Robert G Levenson, Committee Member, Thomas E Spratt, Committee Member, Ira Joseph Ropson, Committee Member.

Subjects/Keywords: neuronal calcium sensor 1; signalplex; myristoylation; dopaminergic signalling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

De Cotiis, D. A. (2009). FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9804

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

De Cotiis, Daniel A. “FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .” 2009. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/9804.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

De Cotiis, Daniel A. “FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .” 2009. Web. 01 Mar 2021.

Vancouver:

De Cotiis DA. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/9804.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

De Cotiis DA. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9804

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

18. Geddes, Rastafa I. THE GUSTATORY INSULAR THALAMOCORTICAL TRACT IS NECESSARY FOR ACQUISITION AND RETENTION OF DRUG-INDUCED REWARD COMPARISONS, BUT NOT LICL-INDUCED TASTE AVERSION .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9564

► This dissertation systematic tested conditioned taste suppression (CTS) of a taste stimulus when repeatedly paired with morphine, cocaine, sucrose, or LiCl in male Sprague-Dawley rats… (more)

▼ This dissertation systematic tested conditioned taste suppression (CTS) of a taste stimulus when repeatedly paired with morphine, cocaine, sucrose, or LiCl in male Sprague-Dawley rats with discrete lesions of the taste thalamus and/or insular primary gustatory cortex (GC). To begin addressing these ideas, we utilized stereotaxic-guided, ibotenic-acid lesions of the GC, or bilateral GCTx, in order to determine the role of the GC in CTS of a taste stimulus when contingently paired with morphine, cocaine, the emetic LiCl, and a known reinforcer such as sucrose (Chapters 2 and 3). At the end of Chapter 3, unilateral lesions of the primary GC was combined either an ipsilateral (Ip-CNTL) or a contralateral (THCx) electrophysiological-guided excitotoxic disruption of the taste thalamus, and tested under the successive negative contrast paradigm. In Chapter 4, rats with asymmetric THCx lesions were tested under drug contrast acquisition, retention, and LiCl-induced conditioned taste aversion (CTA). In Chapter 5, taste-drug induced CTSs were subsequently tested in naïve rats with THCx lesions under cocaine self-administration and cue-induced instrumental responding for morphine in the runway. Taken together, the results of our behavioral experiments suggest that the taste thalamocortical loop is essential for particular types of reward- and some forms of drug-induced CTS, but not innate preference/aversions, eliciting taste stimulated orofacial responses, producing LiCl-CTA or, an association between the taste CS and drug reward (i.g., cue-induced craving), per se. In Chapter 6, the interpretation our findings in terms of affective/cognitive perceptions as the driving forces behind (1) the possible the direction of sensory processing, (2) the manner in which relative value is attribution to relevant stimuli, and (3) the mode of by which behavioral responding (voluntary/autonomic) under specific CS-US pairings. Advisors/Committee Members: Patricia S Grigson Kennedy, Dissertation Advisor/Co-Advisor, Patricia Grigson, Committee Chair/Co-Chair, Ralph Norgren, Committee Member, Robert J Milner, Committee Member, Andras Hajnal, Committee Member, Robert G Levenson, Committee Member, Kevin Douglas Alloway, Committee Member.

Subjects/Keywords: lesions; ibotenic-acid; primary taste cortex; conditioned taste avoidance; suppression; asymmetric

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Geddes, R. I. (2010). THE GUSTATORY INSULAR THALAMOCORTICAL TRACT IS NECESSARY FOR ACQUISITION AND RETENTION OF DRUG-INDUCED REWARD COMPARISONS, BUT NOT LICL-INDUCED TASTE AVERSION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9564

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Geddes, Rastafa I. “THE GUSTATORY INSULAR THALAMOCORTICAL TRACT IS NECESSARY FOR ACQUISITION AND RETENTION OF DRUG-INDUCED REWARD COMPARISONS, BUT NOT LICL-INDUCED TASTE AVERSION .” 2010. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/9564.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Geddes RI. THE GUSTATORY INSULAR THALAMOCORTICAL TRACT IS NECESSARY FOR ACQUISITION AND RETENTION OF DRUG-INDUCED REWARD COMPARISONS, BUT NOT LICL-INDUCED TASTE AVERSION . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/9564.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Geddes RI. THE GUSTATORY INSULAR THALAMOCORTICAL TRACT IS NECESSARY FOR ACQUISITION AND RETENTION OF DRUG-INDUCED REWARD COMPARISONS, BUT NOT LICL-INDUCED TASTE AVERSION . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/9564

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

19. Chandy, Mark. HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6926

► Chromatin condenses DNA and packages it into the nucleus. The fundamental unit of chromatin is the nucleosome, which compacts and forms higher order structures. Chromatin… (more)

▼ Chromatin condenses DNA and packages it into the nucleus. The fundamental unit of chromatin is the nucleosome, which compacts and forms higher order structures. Chromatin structure affects transcription, DNA replication and DNA repair. For gene expression, chromatin is dynamically modulated by chromatin modifying complexes and chromatin remodeling complexes. The histone code hypothesis predicts that modifications not only dictate the inheritance of chromatin states, but also that combinations of modifications recognized by protein-interaction domains are important for recruiting cofactors that alter chromatin structure. For over 40 years, histone acetylation has been associated with gene activation. Moreover, the discovery of histone acetyl transferase (HAT) complexes has implicated acetylation in transcription, DNA repair and even silencing. The SAGA complex is a 1.8 MDa multisubunit HAT complex that is recruited by activator at promoters. As the catalytic subunit of SAGA, Gcn5 acetylates promoter nucleosomes and produces a peaked acetylation profile upon gene induction. Moreover, the Gcn5 bromodomain is required for retention on acetylated nucleosomes. We test the importance of the Gcn5 bromodomain in restricting SAGA acetylation to the promoter using the scanning in vitro chromatin immunoprecipitation assay. The Gcn5 bromodomain does not significantly affect the nucleosomal acetylation profile of SAGA, even when the activator is removed from the array. While the Spt7 bromodomain does not retain SAGA on acetylated nucleosomes in vitro, its evolutionary conservation in yeast suggests that it may help retain SAGA on acetylated nucleosomes in vivo. When tested on phenotypic screens, the Spt7 bromodomain mutant and the Spt7 and Gcn5 double bromodomain mutant have a slight phenotype. The accumulation of acetylated histones at the promoter signals for the recruitment of other cofactors. SAGA and the ATP dependent chromatin remodeler, SWI/SNF functioned cooperatively in the activation of several genes in budding yeast. At the PHO5 promoter, both SAGA and SWI/SNF are important for timely removal of nucleosomes from the promoter. The loss of SWI/SNF results in the accumulation of H3K9 acetylated histones at this promoter, which is also an acetylation site for SAGA. Thus, SAGA acetylation at the promoter may recruit SWI/SNF and promote the displacement of acetylated nucleosomes. We directly test the influence of SAGA acetylation on SWI/SNF nucleosome displacement using several assays on the immobilized nucleosome array in vitro. SWI/SNF not only displaces acetylated nucleosomes, but it also targets promoter acetylated nucleosomes in the absence of activator. More important, SWI/SNF displacement of acetylated nucleosomes correlates with an increase in accessible DNA at the promoter. Advisors/Committee Members: James E Hopper, Committee Chair/Co-Chair, Sergei A Grigoryev, Committee Member, Michael G Fried, Committee Member, Laura Carrel, Committee Member, Jerry L Workman, Committee Chair/Co-Chair, Robert G Levenson, Committee Member.

Subjects/Keywords: SAGA; SWI/SNF; chromatin remodeling; bromodomain

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chandy, M. (2008). HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6926

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chandy, Mark. “HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES .” 2008. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/6926.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chandy, Mark. “HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES .” 2008. Web. 01 Mar 2021.

Vancouver:

Chandy M. HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/6926.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chandy M. HISTONE MODIFICATIONS INFLUENCE CHROMATIN MODIFYING AND CHROMATIN REMODELING COMPLEXES . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6926

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

20. Kivovich, Violetta. Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10519

► Human parvovirus B19 is a ubiquitous infectious agent known to cause erythema infectiosum in children. Numerous clinical observations have also linked the virus to diverse… (more)

▼ Human parvovirus B19 is a ubiquitous infectious agent known to cause erythema infectiosum in children. Numerous clinical observations have also linked the virus to diverse idiopathic conditions such as systemic lupus erythematosus (SLE)-like syndromes, a variety of rheumatic manifestations, liver and kidney disease. Tissues identified as non-permissive for B19 replication have been shown to harbor genomic evidence of B19 infection for extended periods of time. Although such non-permissive cells display an inability to produce viral structural proteins and replicate the viral genome, curiously these same tissues allow for transcription and translation of the B19 non-structural protein 1 (NS1). As the sole chaperone of all major steps in the viral life cycle and mediator of cytotoxicity in mammalian cells, the persistence of NS1 in replication non-permissive tissues may be responsible for many of the non-hematological conditions associated with parvovirus B19 infection. In this dissertation, I examine the mechanism of B19 NS1-induced cytotoxicity. I hypothesize that the endonuclease activity encoded in the B19 NS1 protein is responsible for B19 NS1-induced cytotoxicity in mammalian cells. To examine this hypothesis, I generated a homology model of B19 NS1, which demonstrated the spatial localization and key residues in the endonuclease active site of B19 NS1 as well as the ATP binding region of the protein. Residues in the putative metal coordination motif of the endonuclease active site were mutated in order to abrogate this catalytic function. Abrogation of the endonuclease active site was shown to disrupt B19 NS1-induced cell cycle arrest in the S phase, reduce B19 NS1-induced DNA damage and subsequent apoptotic cell death. The DNA damage induced by B19 NS1 was suggested to be single-strand breaks, as would be expected if the protein were nicking cellular DNA with the endonuclease active site. Together, these experiments showed that the endonuclease activity of B19 NS1 upon cellular DNA is partially responsible for B19 NS1-induced cytotoxicity. An additional amino acid substitution in B19 NS1 was examined for its effect on B19 NS1-induced cytotoxicity. B19 genotypes 1 and 3 have been associated with fulminant hepatitis, in contrast to genotype 2. Substitution I181M, only observed in B19 genotype 2 NS1 proteins, was introduced into a genotype 1 background of NS1. The NS1 protein with the I181M substitution was less toxic to mammalian cells in culture, suggesting that this substitution in genotype 2 NS1 proteins may reduce their ability to kill liver cells and thereby cause fulminant hepatitis. Together, these studies support the hypothesis that direct NS1-induced cellular damage contributes to non-hematological conditions associated with parvovirus B19 infection. Advisors/Committee Members: Mark Kester, Ph D, Dissertation Advisor/Co-Advisor, Mark Kester, Committee Chair/Co-Chair, Stanley J Naides, Committee Member, Robert Harold Bonneau, Committee Member, Robert G Levenson, Committee Member, Leslie Joan Parent, Committee Member.

Subjects/Keywords: homology modeling; B19; NS1; apoptosis; DNA damage; parvovirus; singla-strand breaks

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kivovich, V. (2010). Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10519

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kivovich, Violetta. “Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. .” 2010. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/10519.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kivovich, Violetta. “Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. .” 2010. Web. 01 Mar 2021.

Vancouver:

Kivovich V. Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/10519.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kivovich V. Examination of the mechanism of parvovirus B19 NS1 induced cellular toxicity. . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/10519

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

21. Lewis, Candice. Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores.

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11411

► O6-Alkylguanine-DNA alkyltransferase (AGT) is a highly conserved DNA repair protein, that removes alkyl adducts at the O6-position of guanine in a single irreversible, stoichiometric reaction.… (more)

▼ O6-Alkylguanine-DNA alkyltransferase (AGT) is a highly conserved DNA repair protein, that removes alkyl adducts at the O6-position of guanine in a single irreversible, stoichiometric reaction. AGT is unique among all the other DNA repair pathways as it requires no co-factors or chaperones to carry out DNA repair. O6-Alkylguanine is a highly cytotoxic lesion, and when left un-repaired, leads to G:C to A:T transition mutations. Upon alkyl transfer, AGT continues to bind to DNA and could impede other AGT molecules from repairing DNA. Therefore, degradation might be the only mechanism to remove the alkylated AGT. To study human AGT (hAGT) degradation and intracellular dynamics, we created a Green Fluorescent Protein (GFP)-hAGT fusion and expressed this tagged AGT in Chinese Hamster Ovary (CHO) cells. GFP-hAGT expressing CHO cells enabled Fluorescent Recovery After Photobleaching (FRAP) experiments showing for the first time, the rapid mobility of AGT within the nucleus. When the entire nucleus was bleached, recovery of fluorescence occurred only after 30 minutes, indicating that AGT accumulates in the nucleus over long periods of time, probably soon after synthesis. The addition of GFP at the N-terminus of hAGT changed some physiological features of hAGT. The half life of the alkylated protein changed from 9h for the native form to 26h for the GFP-tagged form. However, the formation of putative Ub-GFP-AGT species was similar to the ubiquitination pattern and time frame, seen in wt hAGT expressed in CHO cells. This finding suggests that the N-end rule pathway for ubiquitin-mediated degradation may not be the only proteolytic pathway regulating degradation of hAGT. Fluorophores were used to characterize a novel 16kDa AGT truncation species detected in both CHO and HeLa cells. The cleavage site of this species was determined to be at codon 50, causing the elimination of three of the four ligands required to bind a zinc atom and maintain structural stability. Despite the truncation of the N-terminus, this 16kDa hAGT species showed significant protection from N-Methyl-N’-Nitro-N-Nitrosoguanidine (MNNG) induced cytotoxicity in Escherichia coli (E.coli). Together with purified protein AGT activity assays, these data indicate that this truncated AGT species retains the ability to repair DNA. This intriguing finding suggests that this truncated species is either part of a previously unknown degradation cycle, or it has a unique role in the cytosol. The biological role of AGT is to protect cells from alkylation damage generated from endogenous as well as environmental sources. However, as a consequence of its biological role, hAGT plays an important part in tumor cells by causing resistance to some chemotherapeutic drugs such as temozolomide or BCNU, by neutralizing the drug induced alkylation damage. Therefore, in order to combat this effect, a series of AGT inhibitors were created previously to inactivate hAGT and increase the efficacy of chemotherapy. O6-Benzylguanine (O6-BG) is one such, potent inhibitor of AGT, which is… Advisors/Committee Members: Kristin Eckert, Dissertation Advisor/Co-Advisor, Kristin Eckert, Committee Chair/Co-Chair, Dr Sreenivas Kanugula, Committee Chair/Co-Chair, Hui Ling Chiang, Committee Member, Ira Joseph Ropson, Committee Member, Robert G Levenson, Committee Member.

Subjects/Keywords: DNA repair; AGT; O6-Benzylguanine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lewis, C. (2010). Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11411

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lewis, Candice. “Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores.” 2010. Thesis, Penn State University. Accessed March 01, 2021. https://submit-etda.libraries.psu.edu/catalog/11411.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lewis, Candice. “Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores.” 2010. Web. 01 Mar 2021.

Vancouver:

Lewis C. Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores. [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 01]. Available from: https://submit-etda.libraries.psu.edu/catalog/11411.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lewis C. Characterization of O6-Alkylguanine-DNA Alkyltransferase Degradation and Labeling with Fluorophores. [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11411

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations