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：
8643226
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/8643226
关键词：
Acute Adenosine Kinase Adverse effects Affect Age Alleles American Animals Beta Cell Biological Models Blood Glucose Breeding Cell Proliferation 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 Islet Cell 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

Acute Adenosine Kinase Adverse effects Affect Age Alleles American Animals Beta Cell Biological Models Blood Glucose Breeding Cell Proliferation 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 Islet Cell 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

展开

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（由适用提供）：当前的2型糖尿病（T2DM）大流行会影响全球超过3.47亿个人，并且是可预见的未来的主要医疗保健。鉴于与T2DM相关的巨大医疗保健伯恩，迫切需要改善疗法。一种理论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尤利克米亚。最近，证明了酶腺苷激酶（ADK）的小分子抑制剂可促进 - 细胞的增殖，而不是其他细胞类型的增殖。（1）这一发现导致ADK抑制剂代表了一种新的糖尿病疗法，通过增加–cell生长来起作用。不幸的是，当前可用的ADK抑制剂具有中枢神经系统副作用，可防止其长期在体内使用。此外，在全球范围内缺乏ADK的动物是不可行的。因此，为了测试ADK的体内函数�-细胞，必须生成一般修改的小鼠，以允许以细胞类型特定和暂时控制的方式禁用ADK表达。该提案描述了这些小鼠的使用来表征ADK的表达模式，并测试是否破坏»细胞内的ADK表达增加了胰岛的复制和质量。这项工作有可能验证一种治疗糖尿病的新理论策略。