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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

基本信息

批准号：
9321887
负责人：
Jixin Zhong
金额：
$ 14.71万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-16 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321887
关键词：
Address Adenosine Adipose tissue Antibodies Antidiabetic Drugs Blood Circulation Blood Glucose CD4 Positive T Lymphocytes CD44 gene Catalytic Domain Cell Count Cell surface Cells Clinical Treatment Complex Data Dependence Detection Development Diabetes Mellitus Dipeptidyl Peptidases Discipline Down-Regulation Euglycemic Clamping Failure Fatty acid glycerol esters Functional disorder Gastric Inhibitory Polypeptide Glucose Goals Grant High Fat Diet Human Hyperglycemia Immune Infiltration Inflammation Inflammatory Inosine Insulin Insulin Resistance Interferon Type II Interferons Interleukin-12 Interleukin-2 Investigation Knock-in Mouse Lead Link Lipids Lipoproteins Maintenance Measures Mediating Metabolic Molecular Molecular Mechanisms of Action Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Pathogenesis Pathway interactions Patients Peripheral Plasma Point Mutation Process Rag1 Mouse Regulation Research Resistance Role SELL gene Scientist Signal Transduction Small Interfering RNA Stimulus Symptoms T-Cell Activation T-Lymphocyte TLR4 gene TNF gene Testing Toll-like receptors Training Up-Regulation Visceral adenosine deaminase base career conventional therapy cytokine diabetes control diabetes mellitus therapy diabetic diabetic patient feeding glucagon-like peptide 1 glucose metabolism glycemic control improved insulin sensitivity mouse model new therapeutic target novel novel therapeutic intervention overexpression peripheral blood public health relevance response translational study

项目摘要

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。无法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和对常规治疗作用的分子机制的理解的差距。该K 01申请的总体目标（近期职业目标）是确定二肽基肽酶4（DPP 4）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代谢性炎症的新型治疗靶点的潜力。在本申请中，我们证实了DPP 4在T2 DM发病机制中的关键作用。我们的总体假设是由三组关键的初步数据驱动的：a）免疫细胞上的DPP 4在糖尿病患者的循环和内脏脂肪组织中上调，与胰岛素抵抗的标志物密切相关，B）Toll样受体/MyD 88途径的激活增加了DPP 4的表达，MyD 88的缺乏通过下调DPP 4改善了肠促胰岛素介导的血糖降低作用。c）DPP 4通过与腺苷脱氨酶（ADA）的催化独立相互作用加剧脂肪炎症和胰岛素抵抗。我们建议测试T细胞表达DPP 4的重要性，作为正在进行的跨学科研究的一部分，这将大大提高我的训练水平，并推动我的职业生涯朝着最终目标发展（成为一名独立的科学家，从事涉及多个学科的转化糖尿病研究）：在目的1中，我们将探索DPP 4在T2 DM中上调的机制，并测试T细胞衍生的DPP 4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/MyD 88途径增加DPP 4的表达。在目标2中，我们假设T细胞DPP 4通过其非催化功能促进炎症和胰岛素抵抗，形成前馈回路以加重T2 DM。DPP 4非催化功能通过与ADA相互作用增强T细胞炎症。本研究将利用DPP 4催化位点点突变的DPP 4-/-小鼠和DPP 4 mut小鼠，分离DPP 4的催化和非催化功能，并剖析DPP 4的非催化功能对糖尿病的贡献。将通过检测DPP 4/ADA相互作用来检查参与机制。总的来说，这项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。该应用程序的成功执行可能会导致T2 DM的新治疗策略。众所周知，抑制DPP 4催化功能调节餐后高血糖症状。在本申请中，我们将测试DPP 4非催化功能促进炎症（糖尿病的重要原因）的假设。靶向DPP 4可改善T2 DM的高血糖和炎症。