Integration of IKK and JNK signals in Insulin Resistance

IKK 和 JNK 信号在胰岛素抵抗中的整合

基本信息

批准号：
8149898
负责人：
Jianping Ye
金额：
$ 30.4万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8149898
关键词：
Address Adverse effects Binding Proteins Cell Nucleus Cytoplasm Cytoplasmic Protein Data Development Disease Drug Delivery Systems Epigenetic Process Funding Gene Targeting General Population Genetic Models Glucose HDAC3 gene Health Histones Inflammation Inflammatory Inflammatory Response Insulin Resistance Knock-out Lead MAPK8 gene Mediating Metabolic Metabolic syndrome Modeling Modification Molecular Molecular Models Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Nuclear Translocation Obesity Oxidative Stress PPAR gamma Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Prevention Protein Subunits Protein-Serine-Threonine Kinases Proteins Regulation Reporting Research Ribosomal Protein S6 Kinase Risk Factors Serine Signal Pathway Signal Transduction Stress TNFRSF5 gene Testing Time Tissues Transactivation Transcription Factor AP-1 Transcriptional Activation Transcriptional Regulation activating transcription factor activating transcription factor 1 base blood glucose regulation design disorder prevention fatty acid metabolism glucose metabolism in vivo inhibitor/antagonist insulin receptor substrate 1 protein insulin sensitivity jun Oncogene lipid metabolism molecular modeling novel p65 public health relevance response synergism

项目摘要

DESCRIPTION (provided by applicant): The serine kinases IKK2 and JNK1 contribute to insulin resistance by phosphorylation of IRS-1. This activity has been widely used to explain insulin resistance for many risk factors including inflammation, lipotoxicity, ER stress and oxidative stress. Our study in the last funding period suggests that S6K and HDACs are targeted by the two serine kinases in the regulation of glucose and lipid metabolism. Our data suggests that IKK2 and JNK1 signals may be integrated in the S6K1 activation in the cytoplasm for IRS-1 inhibition. Their signals may also be combined in the regulation of PPARg activity in the nucleus through HDACs. Based on these observations, we hypothesize that S6K1 and HDACs may mediate signals of IKK2 and JNK1 in the regulation of glucose and lipid metabolism. However, the hypothesis remains to be tested and the details remain to be uncovered. We will address these issues in two specific aims: AIM I: To test that the IKK2-JNK1 signal integration may lead to S6K activation in the cytoplasm; AIM II: To test that the IKK2-JNK1 signal integration may control HDACs function in the nucleus. The results will provide a novel and unified mechanism for IKK2 and JNK1 in the regulation of glucose and fatty acid metabolism. The study may lead to identification of new drug target in prevention and treatment of metabolic syndrome. PUBLIC HEALTH RELEVANCE: Type 2 diabetes has been a major health threat to the general public in US. The treatment and prevention of the disease is limited by our understanding of the molecular mechanism of the diseases. In this study, we will investigate the molecular mechanism by focusing on two molecules IKK2 and JNK1. The study will help us to understand the molecular mechanisms, and to identify new drug target for type 2 diabetes.

描述（由申请人提供）：丝氨酸激酶IKK2和JNK1通过IRS-1的磷酸化导致胰岛素抵抗。这种活性已被广泛用于解释许多危险因素的胰岛素抵抗，包括炎症、脂毒性、内质网应激和氧化应激。我们在上一个资助期的研究表明，S6K 和 HDAC 是调节葡萄糖和脂质代谢的两种丝氨酸激酶的靶标。我们的数据表明，IKK2 和 JNK1 信号可能整合到细胞质中的 S6K1 激活中，从而抑制 IRS-1。它们的信号也可能通过 HDAC 结合起来调节细胞核中的 PPARg 活性。基于这些观察，我们假设 S6K1 和 HDACs 可能介导 IKK2 和 JNK1 信号调节葡萄糖和脂质代谢。然而，该假设仍有待检验，细节仍有待揭晓。我们将通过两个具体目标来解决这些问题：目的一：测试IKK2-JNK1信号整合可能导致细胞质中S6K的激活；目的II：测试IKK2-JNK1信号整合可能控制细胞核中的HDAC功能。该结果将为IKK2和JNK1在葡萄糖和脂肪酸代谢的调节中提供一种新颖且统一的机制。该研究可能有助于确定预防和治疗代谢综合征的新药物靶点。公众健康相关性：2 型糖尿病一直是美国公众的主要健康威胁。该疾病的治疗和预防受到我们对疾病分子机制的理解的限制。在本研究中，我们将重点关注 IKK2 和 JNK1 两个分子来研究其分子机制。该研究将帮助我们了解2型糖尿病的分子机制，并确定新的药物靶点。