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

基本信息

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
项目类别：
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

项目摘要

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）：当前 2 型糖尿病 (T2DM) 的流行影响了全球超过 3.47 亿人，在可预见的未来，这是一个主要的医疗保健问题。鉴于与 T2DM 相关的巨大医疗保健负担，迫切需要改善。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最近，腺苷激酶（ADK）的小分子抑制剂被证明可以促进 ¿ -细胞，但不是其他细胞类型。(1) 这一发现引发了这样的假设：ADK 抑制剂代表了一类新的糖尿病治疗药物，其作用是通过增加 ¿不幸的是，目前可用的 ADK 抑制剂具有中枢神经系统副作用，无法在体内长期使用。此外，全身缺乏 ADK 的动物无法存活。 ADK 内的功能 ¿ -细胞有必要产生转基因小鼠，允许以细胞类型特异性和时间控制的方式破坏 ADK 表达。该提案描述了使用这些小鼠来表征 ADK 的表达模式并测试是否破坏 ADK。 ¿ 内的表达-细胞增加胰岛 ¿ -细胞复制和质量这项工作有潜力进行验证。治疗糖尿病的新治疗策略。