Examining a role for G alpha q in preventing autoimmune disease

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Description (provided by applicant): Encoding G alpha q (Gaq-/-), a member of the heterotrimeric GTPase group, develop autoantibody within 2 months of reconstitution. In chimeric mice made with mixed WT and Gaq-/- BM, activated T cells lacking Gaq accumulate in vivo more rapidly than activated B cells and prior to the appearance of autoantibody. Additionally, older chimeras display increased mortality. This suggests that hematopoietic cells lacking Gaq have a selective advantage over WT hematopoietic cells. Additionally, thymocytes lacking Gaq predominate over WT thymocytes. Our goal is to elucidate how the lack of Gaq leads to development of autoantibody. We hypothesize that thymocytes and T cells lacking Gaq are more resistant to cell death, leading to their accumulation in vivo, which drives autoreactive antibody production by B cells and subsequent autoimmunity. Our aims are (1) to determine if Gaq-/- thymocytes and T cell are more resistant to apoptotic stimuli, leading to their selective survival, (2) to determine whether the absence of the Gaq gene generates activated peripheral CD4+ and CD8+ T cells that are resistant to cell death and accumulate in vivo, and (3) to assess whether Gaq-/- T cells are exclusively responsible for driving the generation of autoimmune disease. By isolating Gaq-/- and WT T cells and thymocytes and subjecting them to various forms of apoptosis-inducing stimuli, we will determine whether Gaq lymphoid cells have a selective survival advantage over WT lymphoid cells. This will also allow us to determine at what stage of development Gaq-/- T cells gain their advantage. We will also examine the expression of several pro- and anti-apoptotic genes to determine whether Gaq-/- T cells are inherently more likely to resist cell death than WT T cells. Finally, we will transfer T and/or B cells from Gaq-/- animals into WT hosts to determine whether one or both cell types are driving the generation of autoimmunity. By completing these aims, we will determine the novel mechanism by which lack of Gaq leads to the generation of autoimmune disease. PUBLIC HEALTH RELEVANCE: By understanding how Gaq controls immune cell survival, we will identify factors that allow for the maintenance of potentially autoreactive T and B cells. This will potentially allow for the identification of new drug targets in treating autoimmune disease, which affects between 14.7 and 23.5 million Americans. Therefore, data generated from this proposal is directly relevant to improving the health of many Americans.