Interrogating the Role of Adenosine Kinase in Islet Beta-Cells

探讨腺苷激酶在胰岛β细胞中的作用

• 批准号: 8480250
• 负责人: Justin Pierce Annes
• 金额: $ 7.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480250
• 关键词: Acute; Adenosine Kinase; Adverse effects; Affect; Age; Alleles; American; Animals; Beta Cell; Biological Models; Blood Glucose; Breeding; Cells; Chemicals; Chimeric Proteins; Chronic; Diabetes Mellitus; Diet; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Excision; Fatty Liver; Fatty acid glycerol esters; Future; Galactosidase; Genes; Genetic Recombination; Health Care Costs; Healthcare; In Vitro; Individual; Insulin; Intervention; Mediating; Modeling; Mus; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Pattern; Perinatal; Pharmaceutical Preparations; Phenotype; Proteins; Rattus; Regimen; Role; Tamoxifen; Testing; Therapeutic; Work; animal breeding; cell growth; cell type; diet and exercise; feeding; improved; in vivo; insulin secretion; interest; islet; kinase inhibitor; mature animal; novel therapeutic intervention; novel therapeutics; pandemic disease; prevent; promoter; public health relevance; recombinase; screening; selective expression; small molecule; treatment strategy; vector

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.

描述（由申请人提供）：目前的2型糖尿病（T2DM）大流行影响全球超过3.47亿人，是可预见未来的主要医疗保健问题。鉴于与T2DM相关的巨大医疗负担，迫切需要改进治疗。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。最近，腺苷激酶（ADK）的小分子抑制剂被证明可以促进细胞增殖，但不能促进其他细胞类型的增殖。(1)这一发现导致了一种假设，即ADK抑制剂代表了一类新的糖尿病治疗药物，通过增加细胞生长发挥作用。不幸的是，目前可用的ADK抑制剂具有中枢神经系统副作用，这阻止了它们在体内的长期使用。此外，ADK globall缺陷的动物不能存活。因此，为了测试ADK在细胞内的体内功能，有必要产生允许ADK表达以细胞类型特异性和时间控制方式被破坏的遗传修饰小鼠。该提案描述了使用这些小鼠来表征ADK的表达模式，并测试破坏ADK在胰岛细胞内的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 一种治疗糖尿病的新的治疗策略。