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You searched for +publisher:"University of Alabama – Birmingham" +contributor:("Roth, Kevin <br>"). Showing records 1 – 3 of 3 total matches.

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1. Moore, Carlene Drucilla. The role of centaurin alpha-1 in the regulation of neuronal differentiation.

Degree: PhD, 2008, University of Alabama – Birmingham

In the nervous system, PI 3-kinase has been implicated in neuronal differentiation. My studies have focused on a candidate neuronal PI 3-kinase target centaurin alpha-1, which binds PtdIns(3,4,5)P3, and is an Arf6 GAP. Centaurin alpha-1 is localized in dendrites, dendritic spines and synapses, and is required for neuronal differentiation and spine morphogenesis. In dissociated neuronal cultures, expression of centaurin alpha-1 enhances dendritic branching, and increases dendritic filopodia, lamellipodia and spine-like protrusions. Expression of centaurin alpha-1 GAP inactive mutant or knocking down centaurin alpha-1 levels using siRNA leads to inhibition of dendritic outgrowth and branching. Manipulations of centaurin alpha-1 also disrupt spine morphogenesis in organotypic brain slice cultures. The effects of centaurin alpha-1 on dendritic development are dependent on it functioning through regulation of Arf6. The constitutively GTPbound mutant Arf6, which reduces dendritic branching on its own, is able to reverse the effects of centaurin alpha-1 overexpression. Conversely, expression of the GDP-bound mutant, Arf6, which enhances branching and outgrowth on its own, can prevent the loss of dendrites induced by centaurin alpha-1 GAP inactive mutant expression or siRNA knock down. Arf6 has been shown to regulate Rac1, and both Arf6 and centaurin alpha- 1 have been proposed to regulate ERK; both Rac1 and ERK have been implicated in neuronal differentiation. Thus, I examined whether centaurin alpha-1 modulates neuronal Rac1 and ERK, to identify candidate downstream effectors of centaurin alpha-1 and Arf6 in neuronal differentiation. ERK and Rac1 activation are enhanced in centaurin alpha-1 over-expressing neurons and this activation is dependent on centaurin alpha-1 GAP activity. As a regulator of Arf6, centaurin alpha-1 has emerged as a candidate to participate in PI 3-kinase regulated Arf6 pathways that control dendritic differentiation and spine morphogenesis.

xiv, 160 p. : ill., digital, PDF file

Neurobiology

Joint Health Sciences

Centaurin alpha-1 P13 kinase Arf6 Dendrites Rac 1 ERK1/2

UNRESTRICTED

Advisors/Committee Members: Theibert, Anne, Floyd, Candice <br>, Pozzo-Miller, Lucas <br>, Roth, Kevin <br>, Wilson, Scott.

Subjects/Keywords: 1-Phosphatidylinositol 3-Kinase <; br>; Adaptor Proteins, Signal Transducing  – metabolism <; br>; Dendrites  – metabolism <; br>; Dendrites  – ultrastructure <; br>; GTPase-Activating Proteins  – metabolism <; br>; Hippocampus  – cytology <; br>; Nerve Tissue Proteins  – metabolism <; br>; Neurons  – metabolism

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

APA (6th Edition):

Moore, C. D. (2008). The role of centaurin alpha-1 in the regulation of neuronal differentiation. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,208

Chicago Manual of Style (16th Edition):

Moore, Carlene Drucilla. “The role of centaurin alpha-1 in the regulation of neuronal differentiation.” 2008. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 07, 2019. http://contentdm.mhsl.uab.edu/u?/etd,208.

MLA Handbook (7th Edition):

Moore, Carlene Drucilla. “The role of centaurin alpha-1 in the regulation of neuronal differentiation.” 2008. Web. 07 Dec 2019.

Vancouver:

Moore CD. The role of centaurin alpha-1 in the regulation of neuronal differentiation. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2008. [cited 2019 Dec 07]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,208.

Council of Science Editors:

Moore CD. The role of centaurin alpha-1 in the regulation of neuronal differentiation. [Doctoral Dissertation]. University of Alabama – Birmingham; 2008. Available from: http://contentdm.mhsl.uab.edu/u?/etd,208

2. McFarland, Braden Cox. Targeting angiogenesis with plasminogen kringle 5.

Degree: PhD, 2009, University of Alabama – Birmingham

The recombinant fifth kringle domain of plasminogen (rK5) has been shown to induce apoptosis of dermal microvessel endothelial cells (MvEC), and this pro-apoptotic effect required rK5 binding to cell surface glucose-regulated protein 78 (GRP78). GRP78 is a member of the heat shock protein family and under certain conditions is expressed on the cell surface. I am interested in identifying new anti-angiogenic therapy for glioblastoma tumors. The efficacy of certain anti-angiogenic therapy can be improved when combined with radiation, and radiation is a standard therapy for glioblastoma tumors; therefore, I investigated the pro-apoptotic effect of rK5 combined with radiation on primary human brain MvEC. I found that treatment of brain MvEC with rK5 induced apoptosis in a dose- and time-dependent manner, and that prior irradiation significantly sensitized (500-fold) the cells to the pro-apoptotic effect of rK5. In both the unirradiated and irradiated MvEC, the rK5-induced apoptosis required the expression of GRP78 and the low density lipoprotein receptor-related protein 1 (LRP1), a scavenger receptor. This was determined by blocking studies with an antibody directed toward GRP78 and with a competitive inhibitor of ligand binding to LRP1, as well as by downregulation studies with small interfering RNA. Also, I found p38 MAP kinase to be a necessary downstream effector of rK5-induced apoptosis, in contrast to Erk and JNK. These data suggest that irradiation sensitizes brain MvEC to rK5-induced apoptosis and that this signal requires LRP1 internalization of GRP78 and the activation of p38 MAP kinase. The physiologic relevance of these findings are supported by my observation that expression of GRP78 protein is upregulated on the brain MvEC in glioblastoma tumor biopsies as compared to the normal brain, suggesting a potential tumor-specific effect of rK5. In addition, in an orthotopic intracerebral xenograft mouse model of malignant glioma, I found that treatment with rK5 significantly decreased tumor volume. Taken together, these in vitro and in vivo data potentially present an important new therapeutic role for rK5 in the treatment of malignant gliomas.

xvi, 124 p. : ill., digital, PDF file

Neurobiology

Joint Health Sciences

Glioma Angiogenesis GRP78 LRP1 Radiation Kringle 5

UNRESTRICTED

Advisors/Committee Members: Gladson, Candece, Brenner, Michael<br>Roth, Kevin<br>Sontheimer, Harald<br>Theibert, Anne.

Subjects/Keywords: Angiogenesis Inhibitors  – metabolism<; br>; Apoptosis<; br>; Glioblastoma  – blood supply<; br>; Neovascularization, Pathologic  – drug therapy<; br>; Plasminogen  – therapeutic use

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

APA (6th Edition):

McFarland, B. C. (2009). Targeting angiogenesis with plasminogen kringle 5. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,399

Chicago Manual of Style (16th Edition):

McFarland, Braden Cox. “Targeting angiogenesis with plasminogen kringle 5.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 07, 2019. http://contentdm.mhsl.uab.edu/u?/etd,399.

MLA Handbook (7th Edition):

McFarland, Braden Cox. “Targeting angiogenesis with plasminogen kringle 5.” 2009. Web. 07 Dec 2019.

Vancouver:

McFarland BC. Targeting angiogenesis with plasminogen kringle 5. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2019 Dec 07]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,399.

Council of Science Editors:

McFarland BC. Targeting angiogenesis with plasminogen kringle 5. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,399

3. Chen, Ping-Chung. The role of USP14 in regulating synaptic development and function of the neuromuscular junctions.

Degree: PhD, 2010, University of Alabama – Birmingham

In the nervous system, the ubiquitin proteasome system (UPS) plays critical roles in regulating a wide diversity of cellular process such as synaptic transmission, axon outgrowth, and synapse development. Although impairment of the UPS is observed in many neurodegenerative diseases, the mechanisms underlying how UPS dysregulation contributes to disease pathogenesis are not known. The proteasome, an approximate 2.5 megadaltons protein complex composed of 19S and 20S assemblies, is the site of ubiquitin-dependent protein degradation. Recent studies have demonstrated dysfunction of 20S core particle in many neurological diseases, however, there have been no studies linking alterations in 19S regulatory particle function to disease. The studies described in this thesis focus on the role of ubiquitin specific protease 14 (Usp14), a deubiquitinating enzyme (DUB) associated with the 19S regulatory particle, in the regulation of the postnatal development of the nervous system. In this thesis study, we first identify an essential role for Usp14 in mediating the postnatal development of the NMJ. Loss of Usp14 does not lead to motor neurons cell death in the spinal cord, but does lead to synaptic developmental deficits at the neuromuscular junction (NMJ) of the ataxia (axJ) mice. Pre-synaptic defects include phosphorylated neurofilament accumulation, nerve terminal sprouting and poor arborization of the motor nerve terminal, while post-synaptic acetylcholine receptor clusters display immature plaque-like morphology. Transgenic restoration of Usp14 exclusively in neurons corrects the structural and functional deficits at the axJ NMJ. Second, we demonstrate that ubiquitin pools maintained by the catalytic activity of Usp14 are required for proper synaptic function and development of the NMJ. Neuronal overexpression of ubiquitin by the Thy1-ubiquitin transgene restores ubiquitin levels in the axJ mice and significantly improves their viability, growth, locomotor motor activities and both structural and functional defects at the axJ NMJ. Our study reveals a crucial role for the proteasome in regulating synaptic function and development at NMJs by stabilizing ubiquitin pools and provides new avenues for developing therapeutic targets of neuromuscular diseases caused by the impairment of the UPS.

1 online resource (xiii, 123 p. : ill., digital, PDF file)

Neurobiology

Joint Health Sciences;

ubiquitin proteasome synapse development Usp14 neuromuscular junctions

UNRESTRICTED

Advisors/Committee Members: Wilson, Scott, Lester, Robin<br>, Marques, Guillermo<br>, Roth, Kevin<br>, Theibert, Anne.

Subjects/Keywords: Neuromuscular Junction  – enzymology<; br>; Neuromuscular Junction  – growth & development<; br>; Proteasome Endopeptidase Complex  – metabolism<; br>; Synapses  – enzymology<; br>; Ubiquitin  – metabolism<; br>; Ubiquitin Thiolesterase  – physiology

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

APA (6th Edition):

Chen, P. (2010). The role of USP14 in regulating synaptic development and function of the neuromuscular junctions. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,992

Chicago Manual of Style (16th Edition):

Chen, Ping-Chung. “The role of USP14 in regulating synaptic development and function of the neuromuscular junctions.” 2010. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 07, 2019. http://contentdm.mhsl.uab.edu/u?/etd,992.

MLA Handbook (7th Edition):

Chen, Ping-Chung. “The role of USP14 in regulating synaptic development and function of the neuromuscular junctions.” 2010. Web. 07 Dec 2019.

Vancouver:

Chen P. The role of USP14 in regulating synaptic development and function of the neuromuscular junctions. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2010. [cited 2019 Dec 07]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,992.

Council of Science Editors:

Chen P. The role of USP14 in regulating synaptic development and function of the neuromuscular junctions. [Doctoral Dissertation]. University of Alabama – Birmingham; 2010. Available from: http://contentdm.mhsl.uab.edu/u?/etd,992

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