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The SH2D5 signaling molecule is a previously uncharacterized adaptor-like protein, containing an N-terminal phosphotyrosine binding (PTB) domain and a noncanonical Src Homology-2 (SH2) domain. With an antibody that I developed, I have shown that SH2D5 is highly enriched throughout adult brain regions. Furthermore, SH2D5 is localized to purkinjie cells in the cerebellum, the cornu ammonis (CA) of the hippocampus and pyramidal cells in the cortex. Despite harbouring two potential phosphotyrosine (pTyr) recognition domains, SH2D5 binds minimally to pTyr ligands. To discover the interaction partners of SH2D5 I conducted an immunoprecipitation/ mass spectrometry (IP/MS) screen from cultured Human Embryonic Kidney (HEK) 293T and Neuro2A cells along with murine brain lysates. These experiments revealed novel binding partners to SH2D5 including a prominent association with the RacGAP protein, Breakpoint Cluster Region protein (BCR), which is also highly expressed in brain. I have defined the interaction between SH2D5 and BCR and show that the PTB domain of SH2D5 engages an NxxF motif located within the N-terminal region of BCR. To address the biological significance of SH2D5, I utilized an siRNA approach to deplete the neuroblastoma cell-line, B35, of iii SH2D5. In these assays, B35 cells display a cell rounding phenotype and grow in a lattice formation. Furthermore, upon SH2D5 depletion these cells display low levels of activated Rac, associated with cell rounding. Taken together, these data reveal the first characterization of the SH2D5 signaling protein, its novel interaction with BCR and phenotype in neuronal-like cells. These data signify a biological function for SH2D5 in neurobiologic signaling perhaps applicable to learning and memory.

The SH2D5 signaling molecule is a previously uncharacterized adaptor-like protein, containing an N-terminal phosphotyrosine binding (PTB) domain and a noncanonical Src Homology-2 (SH2) domain. With an antibody that I developed, I have shown that SH2D5 is highly enriched throughout adult brain regions. Furthermore, SH2D5 is localized to purkinjie cells in the cerebellum, the cornu ammonis (CA) of the hippocampus and pyramidal cells in the cortex. Despite harbouring two potential phosphotyrosine (pTyr) recognition domains, SH2D5 binds minimally to pTyr ligands. To discover the interaction partners of SH2D5 I conducted an immunoprecipitation/ mass spectrometry (IP/MS) screen from cultured Human Embryonic Kidney (HEK) 293T and Neuro2A cells along with murine brain lysates. These experiments revealed novel binding partners to SH2D5 including a prominent association with the RacGAP protein, Breakpoint Cluster Region protein (BCR), which is also highly expressed in brain. I have defined the interaction between SH2D5 and BCR and show that the PTB domain of SH2D5 engages an NxxF motif located within the N-terminal region of BCR. To address the biological significance of SH2D5, I utilized an siRNA approach to deplete the neuroblastoma cell-line, B35, of iii SH2D5. In these assays, B35 cells display a cell rounding phenotype and grow in a lattice formation. Furthermore, upon SH2D5 depletion these cells display low levels of activated Rac, associated with cell rounding. Taken together, these data reveal the first characterization of the SH2D5 signaling protein, its novel interaction with BCR and phenotype in neuronal-like cells. These data signify a biological function for SH2D5 in neurobiologic signaling perhaps applicable to learning and memory.

Thesis (Ph. D.)--University of Chicago, Dept. of Molecular Genetics and Cell Biology, 2001. / Includes bibliographical references. Also available on the Internet.

Thesis (M.A.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains v, 38 p. Includes abstract. Includes bibliographical references (p. 18-21).

Thesis (Ph.D.)--York University, 2008. Graduate Programme in Applied Mathematics. / Typescript. Includes bibliographical references (leaves 225-239). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:NR46003

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 76-80).

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterized by high level of autoantibody detected in the body. This disease is female predominant with a male to female ratio 1: 9. SLE could cause damage to different organ systems and central nervous system is one of them. Patients diagnosed with SLE could suffer from psychiatric problems like cognitive dysfunction, depression and anxiety. Neurogenesis refers to the process by which new neurons are generated. Although it has been widely reported that neurogenesis could be enhanced under pathological conditions such as stroke, Huntington’s disease and epilepsy, study focusing on the relationship between neurogenesis and SLE remains limited. In the present study, by using NZB/W F1 mice as the animal model of SLE, we could demonstrate that there was dramatic increase of neuronal precursor cells at the corpus callosum after the onset of SLE symptoms. Meanwhile, as IBA-1 positive cells and GFAP positive cells also increased significantly there, this suggested inflammation has taken place. I hypothesized there were upregulation of immunological factors after the onset of SLE symptoms and those factors were responsible for the neurogenesis. In my in vitro study, cytokine- interferon gamma (IFN gamma) has been shown to promote neuronal progenitor cells (NPCs) to differentiate into neuronal linage but it did not obviously affect the cell proliferation and migration. For the other cytokine and chemokines, including interleukin-10 (IL-10), interleukin-8 (IL-8), macrophage-derived chemokine (MDC), stromal cell-derived factor 1 alpha (SDF-1alpha) and thymus and activation regulated chemokine (TARC), all of them had no effect on NPC proliferation and differentiation. As far as we know, this is the first study to report SLE could enhance neurogenesis. Concerning the role of inflammation and IFN gamma on the neurogenesis in our case, it should be worth for further investigation, which will benefit future development of novel treatment targeting psychiatric symptoms in SLE. / published_or_final_version / Anatomy / Master / Master of Philosophy

No description available.