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

• 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
• 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

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.

抽象的： 这是一份修订后的拨款申请，题为“糖尿病和糖尿病中受体后胰岛素信号的改变” 胰岛素抵抗。”胰岛素和 IGF-1 通过其同源受体（IR 和 IGF1R）发挥作用，产生广泛的胰岛素抵抗。 多年来，我的实验室一直在研究对体内大多数细胞的代谢和生长影响。 致力于了解这个过程中的中间信号以及这些信号如何导致疾病。 因此，我们具体表征了胰岛素受体底物蛋白在偶联 IR 和 IGF1R 对下游效应系统、PI-3 激酶和 Akt 在 IGF1R 代谢作用中的重要作用 胰岛素和 MAP/mTOR/S6K 激酶通路在生长促进中的作用。 开发胰岛素信号网络的集成模型，其中存在关键的信号节点 差异为胰岛素的不同下游作用提供了补充信息。 节点还提供重要的正向和负向调节位点，可导致胰岛素的改变 最近，我们开始剖析 IR/IGF1R 下游的完整磷酸化蛋白质组， 通过这一点，我们发现了胰岛素/IGF-1信号传导的两种新的叉头转录介质：FoxK1和 FoxK2 从疾病的角度来看，我们还展示了不同的胰岛素抵抗状态如何改变胰岛素。 我们还开发了iPS细胞模型来专注于细胞的识别。 事实上，正如我们的初步数据所示， 来自 T2D iPSC 的成肌细胞表现出下游信号传导和代谢功能的缺陷 体外反映了体内发现的缺陷，更重要的是，这些细胞还表现出失调。 多维磷酸化网络 - 经典胰岛素信号级联的内部和外部。 这笔资助，我们将重点关注两个相互关联的具体目标：1）阐明胰岛素的根本差异 使用靶向和全局磷酸化蛋白质组学在体外研究 T2D 和其他胰岛素抵抗状态中的信号转导 来自正常个体、T2D 患者和患有糖尿病的非糖尿病个体的人 iPS 细胞来源的成肌细胞 我们将评估这些变化如何影响细胞功能并参与胰岛素抵抗。 2) 定义两个新的转录下游调节因子 FoxK1 和 FoxK1 在胰岛素作用中的作用。 我们将鉴定 FoxK1/2 调控的基因，确定它们如何补充其他转录。 我们还将定义胰岛素调节细胞功能的调节因子，以及它们在糖尿病中的作用。 使用 Chip-Seq 调控 FoxK 基因 最后，我们将创建具有组织特异性缺失 FoxK1 的小鼠。 FoxK2 和选择的组合敲除以确定它们在胰岛素调节基因中的互补作用 这些研究将把胰岛素的表达和体内作用提升到一个新的水平。 糖尿病中的信号传导及其改变，提供对基因表达的胰岛素调节的更深入了解 为2型糖尿病及其他胰岛素抵抗性疾病的治疗提供新的思路。