Analysis of Ian 5 Function

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The identification of the Ian5 gene as the candidate Iddm2/lyp gene as has opened a new set of questions addressing the particular function of this gene in lymphopenia and its relation to the development of autoimmune diabetes. The knowledge about of Ian5, and of the other members of this gene family is still fragmentary, but seems to involve common themes, such as the ability to regulate apoptosis, to bind GTP, and to by associated with immune cells. It is not known how these emerging activities of Ian 5 are tied to the development of lymphopenia and type 1 diabetes, and whether both lymphopenia and autoimmune diabetes are merely epiphenomena or are indeed causally linked. Evolutionary divergence of the Ian gene family has further led to the presence of a paralog of Ian5, termed Ian4, in both humans and mice, but not in rats. Here, we investigate the specific function of the first identified candidate iddm2 gene, Ian5, in the development of immune diabetes. Specifically, we will utilize transgenic rescue of the lyp-phenotype in BB-DP rats to establish formal proof that the loss of Ian5 function is the sole cause of lymphopenia and autoimmune diabetic disease; Second, we will generate a mouse model of Ian5 deficiency and test the hypothesis that Ian5 prevents lymphopenia and autoimmune disease by inhibiting apoptosis of regulatory T cells induced by the ART2/Rt6-dependent activation of the P2X7 receptor by ribosylated nucleotides. Third, in order to gain first insights into the molecular interactions that couple Ian5 function to the inhibition of apoptosis and autoimmune disease, we will conduct an in vivo structure-function analysis of Ian5. Results from these experiments are expected to delineate the molecular and pathophysiological mechanism that control the survival of regulatory T cells and lead to autoimmune diabetes.