Regulation of DPP4 and its non-catalytic function in type 2 diabetes

DPP4在2型糖尿病中的调控及其非催化功能

• 批准号: 9414476
• 负责人: Jixin Zhong
• 金额: $ 11.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414476
• 关键词: Regulation; DPP4; its; non; catalytic

 DESCRIPTION (provided by applicant): Despite recent advances in diabetes therapy, diabetes in the majority of patients is poorly controlled. This failure to achieve optimum glycemic control partly results from the limitations in our understanding of diabetes pathophysiology and gaps in understanding molecular mechanisms of action of conventional treatments. The overall objective (immediate career goal) of this K01 application is to identify the implication of dipeptidyl peptidase 4 (DPP4) non-catalytic activity in type 2 diabetes Mellitus (T2DM) and test its potential to be a novel therapeutic target which could limit metabolic inflammation in T2DM. In this application, we posit a key role for DPP4 in the pathogenesis of T2DM. Our overarching hypothesis is driven by three key sets of preliminary data: a) DPP4 on immune cells was up-regulated in both circulation and visceral adipose tissue of diabetic humans, correlating strongly with markers of insulin resistance, b) Activation of Toll-like receptor/MyD88 pathway increased DPP4 expression and deficiency of MyD88 improved incretin-mediated blood glucose lowering effect through down-regulation of DPP4. c) DPP4 exacerbated adipose inflammation and insulin resistance through catalytic independent interaction with adenosine deaminase (ADA). We propose to test the significance of T cell-expressing DPP4 as part of an ongoing inter-disciplinary investigation that will significantly enhance my training and propel my career towards ultimate goal (to be an independent scientist working in translational diabetes research involving multiple disciplines): In Aim 1, we will explore the mechanisms by which DPP4 is up-regulated in T2DM and test the contribution of T cell derived DPP4 to pathogenesis of T2DM. Our hypothesis is that postprandial remnant lipoprotein in T2DM increases DPP4 expression via TLR/MyD88 pathway. In Aim 2, we hypothesize that T cell DPP4 promotes inflammation & insulin resistance through its non-catalytic function, forming a feed-forward loop to exacerbate T2DM. DPP4 non-catalytic function enhances T cell inflammation by interacting with ADA. By using DPP4-/- mice and DPP4mut mice with point mutation in DPP4 catalytic site, we will dissociate DPP4 catalytic and non-catalytic function and dissect the contribution of DPP4 non-catalytic function to diabetes. Involving mechanisms will be examined by detection of DPP4/ADA interaction. Collectively, the experimental findings from this application should help drive new understanding of pathophysiology of T2DM. Successful execution of this application may lead to a new therapeutic strategy for T2DM. It's well-known that inhibition of DPP4 catalytic function modulates postprandial hyperglycemia symptoms. In this application, we will test the hypothesis that DPP4 non-catalytic function promotes inflammation, an important cause of diabetes. Targeting DPP4 may improve both hyperglycemia and inflammation in T2DM.

 描述(由申请人提供)：尽管最近糖尿病治疗取得了进展，但大多数患者的糖尿病控制很差。未能达到最佳血糖水平 控制的部分原因是我们对糖尿病病理生理学的理解的局限性，以及对常规治疗的分子作用机制的了解的差距。这项K01应用的总体目标(近期职业目标)是确定二肽基肽酶4(DPP4)的非催化活性在2型糖尿病(T2 DM)中的意义，并测试其作为限制T2 DM代谢性炎症的新治疗靶点的潜力。在这一应用中，我们假设DPP4在T2 DM的发病机制中起着关键作用。我们的总体假设是由三组关键的初步数据驱动的：a)在糖尿病人的循环和内脏脂肪组织中，免疫细胞上的DPP4上调，与胰岛素抵抗的标志物密切相关；b)Toll样受体/MyD88通路的激活增加了DPP4的表达，MyD88的缺失通过下调DPP4改善了胰岛素介导的降血糖作用。C)DPP4通过与腺苷脱氨酶(ADA)的催化非依赖相互作用而加重脂肪炎症和胰岛素抵抗。我们建议测试T细胞表达DPP4的意义，作为正在进行的跨学科研究的一部分，这将显著加强我的培训并推动我的职业生涯朝着最终目标(成为一名从事涉及多学科的翻译糖尿病研究的独立科学家)迈进：在目标1中，我们将探索DPP4在T2 DM中上调的机制，并测试T细胞来源的DPP4在T2 DM发病机制中的作用。我们的假设是T2 DM患者餐后残余脂蛋白通过TLR/MyD88途径增加DPP4的表达。在目标2中，我们假设T细胞DPP4通过其非催化功能促进炎症和胰岛素抵抗，形成一个前馈环路来加重T2 DM。DPP4非催化功能通过与ADA相互作用增强T细胞炎症。利用DPP4催化位点点突变的DPP4-/-小鼠和DPP4mut小鼠，分离DPP4催化和非催化功能，剖析DPP4非催化功能在糖尿病发病中的作用。将通过检测DPP4/ADA相互作用来检查涉及的机制。总而言之，这一应用的实验结果应该有助于推动对T2 DM病理生理学的新理解。这一应用的成功实施可能会为T2 DM带来一种新的治疗策略。众所周知，DPP4催化功能的抑制会调节餐后高血糖症状。在这项应用中，我们将检验DPP4非催化功能促进炎症的假设，炎症是糖尿病的重要原因。靶向DPP4可改善T2 DM患者的高血糖和炎症反应。