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Vanderbilt University
1.
Young, Summer Elizabeth.
Modulation of thrombin receptor signaling.
Degree: PhD, Pharmacology, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/14534 
► The platelet thrombin receptors Protease-activated receptor 1 (PAR1) and Protease activated receptor 4 (PAR4) stand at the intersection of coagulation and platelet activation. Thrombin receptors…
(more)
▼ The platelet thrombin receptors Protease-activated receptor 1 (PAR1) and Protease activated receptor 4 (PAR4) stand at the intersection of coagulation and platelet activation. Thrombin receptors are thus excellent pharmacological targets for the prevention of thrombosis. PAR1 antagonists show promise in clinical trials for the prevention of stroke, myocardial infarction, and death. However, like all anti-platelet therapeutics, PAR1 antagonism carries an increased risk for bleeding. PAR4, the low affinity thrombin receptor, is the next logical target. However, the field lacks a good pharmacological probe thus the role of PAR4 in thrombosis remains unknown.
Described herein is the characterization of modulators of thrombin receptor signaling by distinct entities. The modulation of PAR1 by Activated protein C, though intriguing, fails to differ from thrombin mediated PAR1 activation. Optimization of a high-throughput screen for novel PAR1 antagonists yielded novel structures for the development of future PAR1 inhibitory compounds. One inhibitory compound, o,p ddd, was found to not only inhibit PAR1 but also PAR4 and collagen mediated platelet activation through complex mechanisms. In addition, the design, synthesis, and characterization of indole based, selective PAR4 antagonists is also described.
Approved: Professor Heidi E. Hamm
Advisors/Committee Members: H. Alex Brown (committee member), P. Jeffrey Conn (committee member), Kathleen L. Gould (committee member), Craig W. Lindsley (committee member), Heidi E. Hamm (committee member), John A. Oates (committee member), Richard M. Breyer (Committee Chair).
Subjects/Keywords: protease-activated receptor; thrombosis; thrombin receptors
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APA (6th Edition):
Young, S. E. (2013). Modulation of thrombin receptor signaling. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14534
Chicago Manual of Style (16th Edition):
Young, Summer Elizabeth. “Modulation of thrombin receptor signaling.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14534.
MLA Handbook (7th Edition):
Young, Summer Elizabeth. “Modulation of thrombin receptor signaling.” 2013. Web. 19 Jan 2021.
Vancouver:
Young SE. Modulation of thrombin receptor signaling. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14534.
Council of Science Editors:
Young SE. Modulation of thrombin receptor signaling. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/14534
Vanderbilt University
2.
Burkewitz, Kristopher.
Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.
Degree: PhD, Pharmacology, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/12205
► Proteostasis is maintained by a complex network of genes and processes which includes core synthesis and degradation machineries as well as chemical and protein chaperones.…
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▼ Proteostasis is maintained by a complex network of genes and processes which includes core synthesis and degradation machineries as well as chemical and protein chaperones. Much of what is known about the function and organization of the proteostasis network stems from analyzing how cells respond to genetic or environmental perturbation of proteomic integrity. Recent evidence points to a critical role for the proteostasis network in survival of hypertonic environments, but the proteotoxic effects of hypertonic stress remain largely undescribed. Employing the many experimental advantages of the nematode C. elegans, we provide the first detailed description of the nature and extent of protein damage caused by hypertonic stress. Misfolding and aggregation of diverse reporters and endogenous proteins are rapid and widespread in vivo. Additionally, we demonstrate that acclimation of C. elegans to a mild hypertonic environment activates unknown proteostasis activities capable of preventing aggregation during extreme hypertonic stress.
To define novel aspects of the hypertonic stress response and extend our understanding of cellular proteostasis strategies, we employ genetic and pharmacological approaches in determining the mechanism by which hypertonic acclimation enhances proteostasis. We hypothesize that chemical chaperones, protein chaperones, proteolysis machineries, and/or protein synthesis must be involved. Surprisingly, hypertonicity- or mutation-induced accumulation of glycerol, an organic osmolyte widely believed to act as a chemical chaperone in vivo, does not directly ameliorate protein damage during stress or aging. Protein chaperone expression is not transcriptionally upregulated. Further, hypertonic stress actually reduces protein degradation, an effect not reversed by acclimation. We demonstrate for the first time that suppression of protein translation during an environmental stress directly enhances proteostasis by preventing aggregation of extant proteins. Combined with recent observations that inhibition of translation extends lifespan and occurs naturally in response to other proteotoxic stressors, this finding suggests that translational reprogramming represents a conserved mechanism by which cells reduce the population of nascent, damage-prone proteins to enhance the availability and effectiveness of pre-existing chaperones.
Advisors/Committee Members: Dr. Richard M. Breyer (committee member), Dr. Hassane S. Mchaourab (committee member), Dr. Daniel C. Liebler (committee member), Dr. Kevin Strange (committee member), Dr. Jerod S. Denton (Committee Chair).
Subjects/Keywords: C. elegans; proteostasis; organic osmolytes; protein aggregation; osmotic stress; hypertonic stress
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APA (6th Edition):
Burkewitz, K. (2012). Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12205
Chicago Manual of Style (16th Edition):
Burkewitz, Kristopher. “Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/12205.
MLA Handbook (7th Edition):
Burkewitz, Kristopher. “Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans.” 2012. Web. 19 Jan 2021.
Vancouver:
Burkewitz K. Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/12205.
Council of Science Editors:
Burkewitz K. Characterization of hypertonic stress-induced protein damage and the cellular mechanisms for defense and repair in C. elegans. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/12205
Vanderbilt University
3.
Yin, Shen.
Allosteric modulation of metabotropic glutamate receptors.
Degree: PhD, Pharmacology, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/14819
► Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors that play important roles in modulating signaling transduction, particularly within the…
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▼ Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu4 belongs to a subfamily of mGlus that is coupled to Gi/o G proteins, and represents a promising target for the treatment of Parkinson’s disease. Allosteric modulators of mGlu4 provide several advantages over the orthosteric ligands in terms of drug discovery. However, the complicated pharmacology of allosteric modulators remain largely unexplored. The ubiquitous autacoid and neuromodulator, histamine, biases the signaling of small molecule positive allosteric modulators of mGlu4 toward calcium-dependent pathways via concomitant activation of histamine H1 receptor. These results suggest that allosteric modulators may exhibit functional selective effects in the presence of signaling convergence. In addition, mGlu2 and mGlu4 form a hetero-complex in native brain tissues, and differentially regulate the efficacies of allosteric modulators in cell lines and at the corticostriatal synapse. These data greatly extend our current understanding of mGlu receptor interaction and function and shed light on the development of allosteric modulators for tissue-specific therapy.
Advisors/Committee Members: Richard M. Breyer (committee member), Roger J. Colbran (committee member), Danny G. Winder (committee member), P. Jeffrey Conn (committee member), Colleen M. Niswender (committee member), Vsevolod V. Gurevich (Committee Chair).
Subjects/Keywords: heterodimerization; functional selectivity; pharmacology; allosteric modulators; mGlu
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APA (6th Edition):
Yin, S. (2013). Allosteric modulation of metabotropic glutamate receptors. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14819
Chicago Manual of Style (16th Edition):
Yin, Shen. “Allosteric modulation of metabotropic glutamate receptors.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14819.
MLA Handbook (7th Edition):
Yin, Shen. “Allosteric modulation of metabotropic glutamate receptors.” 2013. Web. 19 Jan 2021.
Vancouver:
Yin S. Allosteric modulation of metabotropic glutamate receptors. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14819.
Council of Science Editors:
Yin S. Allosteric modulation of metabotropic glutamate receptors. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/14819
Vanderbilt University
4.
Ceddia, Ryan Patrick.
The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control.
Degree: PhD, Pharmacology, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/14790
► Mice carrying a targeted disruption of the prostaglandin E2 E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched…
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▼ Mice carrying a targeted disruption of the prostaglandin E2 E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet induced obesity. While no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3-/- mice gained more weight relative to EP3+/+ mice. Overall, EP3-/- mice had increased epididymal fat mass and adipocyte size; paradoxically a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3-/- mice. The EP3-/- mice had increased macrophage infiltration, TNF-α, MCP-1, IL-6 expression, and necrosis in their epididymal fat pads as compared to EP3+/+ animals. Adipocytes isolated from EP3+/+ or EP3-/- mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3-/- mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared to EP3+/+. EP3-/- mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3-/- mice became hyperglycemic and hyperinsulinemic when compared to EP3+/+ fed HFD, demonstrating a more severe insulin resistance phenotype in EP3-/-. These results demonstrate that when fed a HFD, EP3-/- mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.
Advisors/Committee Members: Richard M. Breyer (committee member), Maureen A. Gannon (committee member), James M. Luther (committee member), Owen P. McGuinness (committee member), Kevin P. Currie (Committee Chair).
Subjects/Keywords: GPCR; knock-out; lipid distribution; lipolysis; metabolism; adipose; adipocyte; pancreas; NSAID; inflammation; triglyceride; free fatty acid; glucose; lipid; islet; mouse; diabetes; EP3; PGE2; prostaglandin; obesity; insulin
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APA (6th Edition):
Ceddia, R. P. (2015). The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14790
Chicago Manual of Style (16th Edition):
Ceddia, Ryan Patrick. “The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14790.
MLA Handbook (7th Edition):
Ceddia, Ryan Patrick. “The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control.” 2015. Web. 19 Jan 2021.
Vancouver:
Ceddia RP. The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14790.
Council of Science Editors:
Ceddia RP. The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/14790
Vanderbilt University
5.
Bartlett, Christina Swan.
Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage.
Degree: PhD, Pharmacology, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/14916
► Hypertension is a prevalent disease affecting one in three adults in the United States. Approximately 25 % of the adult population is either not receiving…
(more)
▼ Hypertension is a prevalent disease affecting one in three adults in the United States. Approximately 25 % of the adult population is either not receiving therapy for their hypertension or is unable to control their blood pressure with current therapies, making treatment of hypertension an important public health goal. In blood pressure regulation, PGE2 can act in a pro-hypertensive or anti-hypertensive manner. It has been demonstrated that EP2 and EP4 receptors mediate the vasodepressor actions of PGE2 and EP1 and EP3 receptors mediate the vasopressor actions of PGE2. Additionally, PGE2 and the EP1 receptor have been demonstrated to mediate at least part of the actions of angiotensin II.
I sought to determine the contribution of EP1 and/or EP3 receptors to hypertensive end-organ damage and diabetic nephropathy. In this dissertation, I utilize mice with genetic disruption of EP1 or EP3 receptors and characterize the outcomes of several models of hypertensive organ damage. In the Nphx/DOCA-NaCl/Ang II model of hypertension, I have demonstrated that disruption of EP1 or EP3 can afford substantial protection from end-organ damage and reduce incidence of mortality. The beneficial effects of EP1 disruption, and likely EP3 disruption, appear to be a result of reduction in MAP in this model. The use of another model involving uninephrectomy and Ang II on a 129S6 background suggests the EP1 receptor plays an important role in hypertensive renal disease independent of blood pressure reduction. Furthermore, genetic disruption of EP1 protected eNOS-/- mice from diabetes-induced proteinuria, independent of blood pressure reduction.
In summary, the data presented in this dissertation advances our knowledge of the role of EP1 and EP3 receptors in hypertension and subsequent sequalae and demonstrate a detrimental role of EP1 in this disease. Targeting the EP1 receptor may be a viable pharmaceutical treatment strategy for hypertension and subsequent organ damage.
Advisors/Committee Members: Richard M. Breyer (committee member), Vsevolod V. Gurevich (committee member), Ambra Pozzi (committee member), Alfred L. George, Jr. (committee member), Brian E. Wadzinski (Committee Chair).
Subjects/Keywords: Prostaglandin; Receptor; Hypertension; Diabetes
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APA (6th Edition):
Bartlett, C. S. (2012). Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14916
Chicago Manual of Style (16th Edition):
Bartlett, Christina Swan. “Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14916.
MLA Handbook (7th Edition):
Bartlett, Christina Swan. “Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage.” 2012. Web. 19 Jan 2021.
Vancouver:
Bartlett CS. Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14916.
Council of Science Editors:
Bartlett CS. Role of the prostaglandin E2 receptor EP1 in hypertensive end-organ damage. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/14916
Vanderbilt University
6.
Huang, Xuan.
Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14755
► Epilepsy is a neurological disorder affecting almost one percent of the population, and genetic epilepsy are those caused by a presumed or unknown genetic factor(s).…
(more)
▼ Epilepsy is a neurological disorder affecting almost one percent of the population, and genetic epilepsy are those caused by a presumed or unknown genetic factor(s). Mutations in GABAA receptors, pentameric chloride ion channels mediating fast inhibitory neurotransmission, have been identified in patients and families with epilepsy and found to cause epilepsy in animal models. The majority of synaptic GABAARs are αβγ type receptors composed of two α, two β and one γ2 subunits, and half of these epilepsy-associated GABAAR mutations are located in γ2 subunits encoded by the GABRG2 gene. A better understanding of how different types of epilepsy-associated GABRG2 mutations affect receptor trafficking and channel function, and how these mutations cause epilepsy in mouse models, will facilitate future epilepsy diagnosis as well as treatments. Here we have studied three different types of mutations represented by GABRG2(N79S, R82Q, and P83S), GABRG2(Q40X), and GABRG2(Q390X), in cultured HEK cells or animal models. We found that missense mutations located in receptor interface will disrupt receptor assembly and trafficking, which may be improved by slowing receptor biogenesis. We found that nonsense mutations showing loss of function could be partially rescued using gentamicin-induced stop codon read-through. Finally we showed that gene-target therapy could reverse the seizure phenotype in a mouse model carrying a detrimental mutation with dominant negative effects. To conclude, we have shown different molecular mechanisms are associated with these mutations, and distinct mutation-specific therapy may be potentially developed for future treatments.
Advisors/Committee Members: Richard M. Breyer (committee member), Kevin C. Ess (committee member), Robert L. Macdonald (committee member), Alfred L. George (Committee Chair), Bruce D. Carter (Committee Chair).
Subjects/Keywords: GABA(A) receptors; GABRG2; genetic epilepsy; mutation; therapy
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APA (6th Edition):
Huang, X. (2014). Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14755
Chicago Manual of Style (16th Edition):
Huang, Xuan. “Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14755.
MLA Handbook (7th Edition):
Huang, Xuan. “Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.” 2014. Web. 19 Jan 2021.
Vancouver:
Huang X. Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14755.
Council of Science Editors:
Huang X. Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14755
Vanderbilt University
7.
Yu, Zheyong.
Discovery of a novel lipoxygenase pathway in skin.
Degree: PhD, Pharmacology, 2005, Vanderbilt University
URL: http://hdl.handle.net/1803/14334
► Lipoxygenase (LOX) are non-heme iron dioxygenases that form fatty acid hydroperoxides used in membrane remodeling and cell signaling. Mammalian epidermal LOX type 3 (eLOX3) is…
(more)
▼ Lipoxygenase (LOX) are non-heme iron dioxygenases that form fatty acid hydroperoxides used in membrane remodeling and cell signaling. Mammalian epidermal LOX type 3 (eLOX3) is distinctive in totally lacking this typical oxygenase activity. Surprisingly, genetic evidence has linked mutations in either eLOX3 or a co-localizing enzyme, 12R-LOX, to an inherited skin disease, non-bullous congenital ichthyosiform erythroderma (NCIE), in which there is a defect in the normal skin permeability barrier (Hum. Mol. Gen. 11, 107-113). Here I identify a logical link of the biochemistry to the genetics. eLOX3 functions as a hydroperoxide isomerase utilizing the product of 12R-LOX, 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE), as the preferred substrate. Using HPLC, GC-MS, NMR and CD spectroscopy, I demonstrated that eLOX3 converts 12R-HPETE to a specific epoxyalcohol, 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, and 12-ketoeicosatetraenoic acid in a 2:1 ratio. eLOX3 appears to be unique among LOX enzymes in using the ferrous form of the catalytic iron as the active species, initiating reaction by a one electron reduction of the substrate hydroperoxide and completing reaction by rebound hydroxylation to form the epoxyalcohol product. I analyzed the effect of the naturally occurring mutations identified in NCIE on eLOX3 and 12R-LOX catalytic activity; the lipoxygenase activity of 12R-LOX and the hydroperoxide isomerase activity of eLOX3 were totally eliminated. I further demonstrated that the epoxyalcohol formed by human eLOX3 is metabolized by soluble epoxide hydrolase in human keratinocytes to a single trihydroxy isomer, 8R,11S,12R-trihydroxyeicosa-5Z,9E,14Z-trienoic acid. Both the epoxyalcohol and its triol hydrolysis product were then tested for activity in activation of peroxisome proliferator-activated receptors (PPARs). Each selectively caused induction of PPARalpha-dependent transcription with similar activity to 8S-hydroxyeicosatetraenoic acid, a PPARalpha specific agonist. Because human and mouse express a different spectrum of LOX enzymes in skin, I also investigated the substrate selectivity of mouse eLOX3. It uses the product of mouse 8-LOX as its preferred substrate, a coupling consistent with the specific expression of 8-LOX in mouse skin. My results provide strong biochemical evidence for the existence of a novel LOX pathway. Loss of this pathway may contribute to a reduced differentiation in keratinocytes and pathogenesis of NCIE.
Advisors/Committee Members: Alan R. Brash (committee member), Richard M. Breyer (committee member), H. Alex Brown (committee member), Diane S. Keeney (committee member), Jason D. Morrow (Committee Chair).
Subjects/Keywords: lipoxygenase; ichthyosis; skin; epoxyalcohol; hepoxilin; PPAR
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APA ·
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APA (6th Edition):
Yu, Z. (2005). Discovery of a novel lipoxygenase pathway in skin. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14334
Chicago Manual of Style (16th Edition):
Yu, Zheyong. “Discovery of a novel lipoxygenase pathway in skin.” 2005. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14334.
MLA Handbook (7th Edition):
Yu, Zheyong. “Discovery of a novel lipoxygenase pathway in skin.” 2005. Web. 19 Jan 2021.
Vancouver:
Yu Z. Discovery of a novel lipoxygenase pathway in skin. [Internet] [Doctoral dissertation]. Vanderbilt University; 2005. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14334.
Council of Science Editors:
Yu Z. Discovery of a novel lipoxygenase pathway in skin. [Doctoral Dissertation]. Vanderbilt University; 2005. Available from: http://hdl.handle.net/1803/14334
Vanderbilt University
8.
Sun, Xiaofei.
Studying the role of endocannabinoid signaling in reproduction.
Degree: PhD, Pharmacology, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/13018
► Marijuana is the most commonly used illicit drug, and its major active component, Δ9-tetrahydrocannabinol (Δ9-THC) exert its functions by targeting cannabinoid receptors, CNR1 and CNR2.…
(more)
▼ Marijuana is the most commonly used illicit drug, and its major active component, Δ9-tetrahydrocannabinol (Δ9-THC) exert its functions by targeting cannabinoid receptors, CNR1 and CNR2. There receptors are also targeted by endocannabinoids, including anandamide.
In this dissertation, we show that genetic loss of Faah, which encodes fatty acid amide hydrolase (FAAH), results in elevated levels of anandamide, an endocannabinoid, in the male reproductive system, leading to compromised fertilizing capacity of sperm. This defect is rescued by superimposing deletion of cannabinoid receptor 1 (Cnr1). Retention of Faah-/- sperm on the egg zona-pellucida provides evidence that sperm’s capacity to penetrate the zona barrier is dampened by elevated anandamide levels. Collectively, the results show that aberrant endocannabinoid signaling via CNR1 impairs normal sperm function. Besides unveiling a new regulatory mechanism of sperm function, this study has clinical significance in male fertility.
Exposure to marijuana during pregnancy has adverse effects on placentation. Using mice as a model, we found that the endocannabinoid system is also present on the ectoplacental cone and spongiotrophoblast cells in placentas. We also observed that aberrant endocannabinoid signaling confers premature trophoblast stem cell differentiation, and defective trophoblast development and invasion. These defects are reflected in retarded fetal development and elevated spontaneous pregnancy loss. Because the endocannabinoid system is conserved across species, including humans, our study suggests that endocannabinoid signaling is critical to placentation and pregnancy success in humans.
Collectively, my work demonstrated that appropriate endocannabinoid signaling is critical for both male and female reproductive functions.
Advisors/Committee Members: Sudhansu K. Dey (committee member), Sanjoy K. Das (committee member), Lawrence J. Marnett (committee member), David L. Hachey (committee member), Richard M. Breyer (Committee Chair).
Subjects/Keywords: Placentation; Uterus; Endocannabinoids; Testis; Reproduction
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APA (6th Edition):
Sun, X. (2010). Studying the role of endocannabinoid signaling in reproduction. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13018
Chicago Manual of Style (16th Edition):
Sun, Xiaofei. “Studying the role of endocannabinoid signaling in reproduction.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/13018.
MLA Handbook (7th Edition):
Sun, Xiaofei. “Studying the role of endocannabinoid signaling in reproduction.” 2010. Web. 19 Jan 2021.
Vancouver:
Sun X. Studying the role of endocannabinoid signaling in reproduction. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/13018.
Council of Science Editors:
Sun X. Studying the role of endocannabinoid signaling in reproduction. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/13018
. 
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