Analysis of Ian 5 Function

Ian 5基因作为候选Iddm 2/lyp基因的鉴定开启了一组新的问题，解决了该基因在淋巴细胞减少症中的特定功能及其与自身免疫性糖尿病发展的关系。关于Ian 5和该基因家族的其他成员的知识仍然是零碎的，但似乎涉及共同的主题，例如调节细胞凋亡、结合GTP以及与免疫细胞相关的能力。目前尚不清楚Ian 5的这些新出现的活动如何与淋巴细胞减少症和1型糖尿病的发展联系在一起，以及淋巴细胞减少症和自身免疫性糖尿病是否只是附带现象或确实存在因果关系。伊恩基因家族的进化分歧进一步导致了人类和小鼠中存在一个名为伊恩4的伊恩5基因，但在大鼠中没有。在这里， 我们研究了第一个被鉴定的候选iddm 2基因Ian 5在免疫性糖尿病发展中的特异性功能。具体而言，我们将利用BB-DP大鼠中lyp-phenotype的转基因拯救来建立Ian 5功能丧失是淋巴细胞减少症和自身免疫性糖尿病的唯一原因的正式证据;第二、我们将产生Ian 5缺陷的小鼠模型，并检验Ian 5通过抑制由ART 2/Rt 6诱导的调节性T细胞凋亡来预防淋巴细胞减少症和自身免疫性疾病的假设。核糖基化核苷酸对P2 X7受体的依赖性激活。第三，为了获得对Ian 5功能与抑制细胞凋亡和自身免疫性疾病的分子相互作用的初步见解，我们将对Ian 5进行体内结构-功能分析。这些实验的结果有望阐明控制调节性T细胞存活并导致自身免疫性糖尿病的分子和病理生理机制。

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.