Molecular mechanisms of dysfunctional prostaglandin signaling in the beta-cell

β细胞中前列腺素信号传导功能障碍的分子机制

基本信息

批准号：
8751626
负责人：
Michelle E Kimple
金额：
$ 30.51万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751626
关键词：
Arachidonic Acids Arrestins Beta Cell Binding Biochemical Blood Circulation Blood Glucose C-terminal Caring Cell membrane Cell physiology Cells Child Chronic Disease Clinical Research Complex Conflict (Psychology)Coupled Coupling Cyclooxygenase Inhibitors Data Diabetes Mellitus Diabetes prevention Diabetic mouse Diagnosis Dinoprostone Eicosanoids Enzymes Failure Family Fatty Acids Functional disorder GTP-Binding Proteins Glucose Glucose Intolerance Goals Hormones Human Human Genome Individual Inflammation Mediators Inflammatory Insulin Knowledge Left Link Literature Longevity Mediating Mediator of activation protein Membrane Metabolism Methods Molecular Mus Non-Insulin-Dependent Diabetes Mellitus PTGS2 gene Pancreas Pathway interactions Patients Phospholipase A2 Phospholipids Play Prevention therapy Production Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Family Protein Isoforms Proteins Public Health RNA Splicing Rattus Research Role Signal Pathway Signal Transduction Testing Therapeutic Variant Work autocrine base cell growth cellular targeting cyclooxygenase 2 diabetic diabetic patient improved inhibitor/antagonist innovation insulin secretion interest islet lifetime risk member mouse genome novel paracrine prevent protein complex public health relevance receptor receptor binding response signal processing

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a costly and complex chronic illness and a serious public health problem. The children of today have an overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods for preventing T2D and identifying and properly treating T2D patients is very timely and of great significance. The pathophysiology of T2D is increasingly being linked with inflammatory molecules such as prostaglandin E2 (PGE2), a major arachidonic acid metabolite. Beta-cells themselves express all of the enzymes required for synthesis of PGE2, which is thought to act in an autocrine or paracrine fashion to regulate insulin secretion and possibly even beta-cell growth, proliferation, and survival. Even with the clear importance of this pathway in the normal and dysfunctional beta-cell, few studies have explored the impact of modulating the production or signaling of PGE2 at the level of the beta-cell, in part because of insufficient knowledge of th molecular mechanisms important in these pathways. Our long-term goal is to fully characterize the PGE2 synthesis and signaling pathways in the normal and diabetic beta-cell, determining steps that become dysfunctional in the diabetic state, and ultimately modulating these steps for preventative and therapeutic purposes. The overall objective of this work is to elucidate critical molecular interactions at distinct steps that have remained relatively uncharacterized, with the rationale that in gaining a complete understanding of this important beta-cell signaling pathway, we will be better able to target the dysfunctional beta-cell in T2D prevention and therapy using novel and innovative approaches. Our central hypothesis is that the PGE2 synthesis and signaling pathway is a critical mediator of diabetic beta-cell dysfunction and can be specifically targeted at one or more key steps besides the well-studied cyclooxygenase-2 (COX-2; or prostaglandin-endoperoxidase synthase 2, PTGS2) step. We will test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following three specific aims: (1) Identify the role of arachidonic acid membrane incorporation and release in diabetic beta-cell dysfunction; (2) Determine the role of C-terminal splice variants of the EP3 isoform of the PGE2 receptor in coupling to G-protein signaling partners; and (3) Elucidate the signaling mechanisms downstream of EP3 in promoting beta-cell function, replication, and survival. With the completion of these aims, we anticipate a much more complete understanding of the pathway from arachidonic acid to PGE2 and other metabolites, including how PGE2 activation of its cellular receptor impacts on the diabetic beta-cell. Such results are anticipated to have an important positive impact on the field, as in delineating this long-known but relatively uncharacterized pathway we may be able to meld the discrepant results in the literature and reveal and confirm new targets for the prevention and therapy of T2D.

描述（由申请人提供）：2 型糖尿病 (T2D) 是一种昂贵且复杂的慢性疾病，也是一个严重的公共卫生问题。今天的孩子一生中罹患糖尿病的总体风险接近 50%。因此，开发预防T2D的新方法以及识别和正确治疗T2D患者非常及时且具有重要意义。 T2D 的病理生理学越来越多地与炎症分子相关，例如前列腺素 E2 (PGE2)（一种主要的花生四烯酸代谢物）。 β 细胞本身表达合成 PGE2 所需的所有酶，人们认为 PGE2 以自分泌或旁分泌方式发挥作用，调节胰岛素分泌，甚至可能调节 β 细胞的生长、增殖和存活。即使该通路在正常和功能失调的 β 细胞中具有明显的重要性，但很少有研究探讨在 β 细胞水平上调节 PGE2 的产生或信号传导的影响，部分原因是对分子机制的了解不足在这些途径中很重要。我们的长期目标是充分表征正常和糖尿病β细胞中的PGE2合成和信号通路，确定在糖尿病状态下变得功能失调的步骤，并最终调节这些步骤以达到预防和治疗的目的。这项工作的总体目标是阐明相对未表征的不同步骤中的关键分子相互作用，其基本原理是，在全面了解这一重要的 β 细胞信号传导途径后，我们将能够更好地针对功能失调的 β-细胞信号通路。细胞在 T2D 预防和治疗中使用新颖和创新的方法。我们的中心假设是，PGE2 合成和信号传导途径是糖尿病 β 细胞功能障碍的关键介质，除了经过充分研究的环氧合酶-2（COX-2；或前列腺素内过氧化物酶合酶）之外，还可以专门针对一个或多个关键步骤2、PTGS2)步骤。我们将测试我们的中心假设，从而通过追求以下三个具体目标来实现本申请的目标：（1）确定花生四烯酸膜掺入和释放在糖尿病β细胞功能障碍中的作用； (2) 确定 PGE2 受体 EP3 亚型的 C 端剪接变体在与 G 蛋白信号传导伴侣偶联中的作用； (3) 阐明 EP3 下游促进 β 细胞功能、复制和存活的信号传导机制。随着这些目标的完成，我们预计会对从花生四烯酸到 PGE2 和其他代谢物的途径有更全面的了解，包括 PGE2 激活其细胞受体如何影响糖尿病 β 细胞。这样的结果是预料之中的对该领域产生重要的积极影响，例如描绘这个众所周知但相对通过研究未表征的途径，我们或许能够融合文献中不同的结果，并揭示和确认 T2D 预防和治疗的新目标。