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Alterations in Post-Receptor Insulin Signaling in Diabetes and Insulin Resistance

糖尿病和胰岛素抵抗中受体后胰岛素信号的改变

基本信息

批准号：
10490337
负责人：
C RONALD KAHN
金额：
$ 59.26万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490337
关键词：
1-Phosphatidylinositol 3-Kinase Affect Applications Grants Attention Cell Nucleus Cell model Cell physiology Cells ChIP-seq Complement Coupling Data Defect Development Diabetes Mellitus Diet Disease Environmental Risk Factor Exclusion FOXO1A gene FRAP1 gene Fatty acid glycerol esters Foxes Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genomics Goals Grant Growth Human IGF1R gene In Vitro Individual Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Insulin-Like Growth Factor I Knock-out Lead Link Liver MAPK8 gene Mediating Metabolic Metabolic syndrome Metabolism Modeling Molecular Profiling Mouse Strains Mus Muscle Myoblasts Non-Insulin-Dependent Diabetes Mellitus Nuclear Pathway interactions Patients Phosphorylation Phosphotransferases Population Process Proteins Proteomics Publications Regulation Role Signal Pathway Signal Transduction Site System Tissues Work cell growth regulation combinatorial diabetes mellitus therapy gut microbiome human disease in vivo induced pluripotent stem cell insight insulin mediators insulin regulation insulin sensitivity insulin signaling non-diabetic novel novel therapeutics phosphoproteomics receptor receptor coupling stress kinase transcription factor

项目摘要

Abstract: This is a revised grant application entitled “Alterations in Post-Receptor Insulin Signaling in Diabetes and Insulin Resistance.” Insulin and IGF-1 acting via their cognate receptors (IR and IGF1R) to produce a wide range of metabolic and growth effects on most cells in the body. Over many years, work from my lab has been devoted to understanding the intermediate signals in this process and how these may be altered in disease. Thus, we have characterized extensively the roles of insulin receptor substrate proteins in coupling IR and IGF1R to downstream effector systems, the important role of PI-3 kinase and Akt in the metabolic actions of insulin, and effects of MAP/mTOR/S6K kinase pathway in growth promotion. These studies have led to development of an integrated model of the insulin signaling network in which there are critical nodes of signal divergence that provide complementary information to different downstream actions of insulin. These critical nodes also provide important sites of positive and negative regulation that can lead to alterations of insulin action in disease. Recently, we have begun to dissect the full phosphoproteome downstream IR/IGF1R and, through this, have identified two new Forkhead transcriptional mediators of insulin/IGF-1 signaling, FoxK1 and FoxK2. From a disease perspective, we have also shown how different insulin resistant states alter the insulin signaling network in different tissues. We have also developed iPS cell models to focus on identification of cell autonomous components of insulin resistance in human disease. Indeed, as shown in our preliminary data, myoblasts derived from T2D iPSCs demonstrate defects in downstream signaling and metabolic function in vitro mirroring the defects found in vivo. More importantly, these cells also show dysregulation of a multidimensional phosphorylation network - both inside and outside the classical insulin signaling cascade. In this grant, we will focus on two interrelated specific aims: 1) Elucidate the fundamental differences in insulin signaling in T2D and other insulin resistant states in vitro using targeted and global phosphoproteomics of human iPS cell-derived myoblasts from normal individuals, T2D patients and non-diabetic individuals with insulin resistance. We will assess how these changes affect cellular function and participate in insulin resistance. 2) Define the role of two new downstream transcriptional regulators in insulin action, FoxK1 and FoxK2. We will identify the genes regulated by FoxK1/2, determine how they complement other transcriptional regulators in insulin regulation of cellular function, and how they are altered in diabetes. We will also define FoxK regulated genes using Chip-Seq. Finally, we will create mice with tissue specific deletion of FoxK1, FoxK2 and selected combinatorial knockouts to define their complementary roles in insulin-regulated gene expression and insulin action in vivo. Together these studies will lead to a new level of understanding insulin signaling and its alterations in diabetes, provide deeper understanding of insulin regulation of gene expression and provide new points for therapy of type 2 diabetes and other insulin resistant disorders.

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