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）：尽管糖尿病治疗最近取得了进展，但大多数患者的糖尿病控制不佳。未能达到最佳血糖 控制部分归因于我们对糖尿病病理生理学理解的局限性以及对传统治疗作用分子机制理解的差距。该 K01 申请的总体目标（近期职业目标）是确定二肽基肽酶 4 (DPP4) 非催化活性对 2 型糖尿病 (T2DM) 的影响，并测试其作为限制 T2DM 代谢炎症的新型治疗靶点的潜力。在此应用中，我们假设 DPP4 在 T2DM 发病机制中发挥关键作用。我们的总体假设是由三组关键的初步数据驱动的：a) 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，而 MyD88 的缺乏则通过改善肠促胰素介导的血糖降低作用。 DPP4 的下调。 c) DPP4 通过与腺苷脱氨酶 (ADA) 的催化独立相互作用加剧了脂肪炎症和胰岛素抵抗。我们建议测试表达 T 细胞的 DPP4 的重要性，作为正在进行的跨学科研究的一部分，这将显着增强我的培训并推动我的职业生涯迈向最终目标（成为一名从事涉及多个学科的转化糖尿病研究的独立科学家）：在目标 1 中，我们将探索 DPP4 在 T2DM 中上调的机制，并测试 T 细胞衍生的 DPP4 对糖尿病发病机制的贡献。 T2DM。我们的假设是，T2DM 中的餐后残余脂蛋白通过 TLR/MyD88 途径增加 DPP4 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，形成前馈循环，从而加剧 T2DM。 DPP4 非催化功能通过与 ADA 相互作用增强 T 细胞炎症。通过使用DPP4催化位点点突变的DPP4-/-小鼠和DPP4mut小鼠，我们将分离DPP4催化和非催化功能，并剖析DPP4非催化功能对糖尿病的贡献。将通过检测 DPP4/ADA 相互作用来检查涉及的机制。总的来说，该应用的实验结果应有助于推动对 T2DM 病理生理学的新认识。该应用的成功执行可能会带来 T2DM 的新治疗策略。众所周知，抑制 DPP4 催化功能可调节餐后高血糖症状。在此应用中，我们将测试 DPP4 非催化功能促进炎症（糖尿病的重要原因）这一假设。靶向 DPP4 可能会改善 T2DM 的高血糖和炎症。