Interrogating the Role of Adenosine Kinase in Islet Beta-Cells

描述(申请人提供)：目前的2型糖尿病(T2 DM)大流行影响着全球超过3.47亿人，在可预见的未来是一个主要的医疗保健问题。鉴于与T2 DM相关的巨大医疗负担，迫切需要改进治疗方法。一种治疗策略是通过增加个体的细胞质量和胰岛素分泌能力来维持正常血糖。最近，腺苷激酶(ADK)的小分子抑制剂被证明可以促进细胞的增殖，但不能促进其他类型的细胞的增殖。(1)这一发现导致了一种假设，即ADK抑制剂代表了一种新的糖尿病治疗药物，其功能是通过促进细胞生长来发挥作用。不幸的是，目前可用的ADK抑制剂具有中枢神经系统副作用，阻碍了它们在体内的长期使用。此外，缺乏ADK的动物是不能存活的。因此，为了测试ADK在细胞内的体内功能，有必要培育出允许ADK表达以细胞类型特异性和时间控制的方式被干扰的转基因小鼠。这项建议描述了利用这些小鼠来表征ADK的表达模式，并测试在细胞内干扰ADK表达是否会增加胰岛细胞的复制和质量。这项工作有可能验证 治疗糖尿病的新治疗策略。

DESCRIPTION (provided by applicant): The current type 2 diabetes (T2DM) pandemic affects more than 347 million individuals worldwide and is a major healthcare concern for the foreseeable future. Given the enormous healthcare burden associated with T2DM, there is an urgent need for improved therapies. One therapeutic strategy is to maintain euglycemia by increasing an individual's ¿-cell mass and insulin secretion capacity. Recently, small molecule inhibitors of the enzyme adenosine kinase (ADK) were demonstrated to promote the proliferation of ¿-cell but not other cell types.(1) This discovery has led to the hypothesis that ADK inhibitors represent a new class of diabetes therapeutics that function by increasing ¿-cell growth. Unfortunately, the ADK inhibitors that are currently available have central nervous system side-effects that prevent their long-term use in vivo. In addition, animals that are globall deficient in ADK are nonviable. Therefore, to test the in vivo function of ADK within ¿-cells it wa necessary to generate genetically modified mice that allow ADK expression to be disrupted in a cell-type specific and a temporally controlled manner. This proposal describes the use of these mice to characterize the expression pattern of ADK and to test if disrupting ADK expression within ¿-cells increases islet ¿-cell replication and mass. This work has the potential to validate a new therapeutic strategy for the treatment of diabetes.