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.

摘要： 这是一份修订后的拨款申请，题为“糖尿病和糖尿病患者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)产生广泛的 对体内大多数细胞的新陈代谢和生长的影响范围。多年来，我实验室的工作一直是 致力于了解这一过程中的中间信号以及这些信号在疾病中可能如何改变。 因此，我们广泛研究了胰岛素受体底物蛋白在IR和IR偶联中的作用。 IGF1R对下游效应系统、PI-3激酶和Akt代谢作用的影响 胰岛素，以及MAP/mTOR/S6K激酶通路在促生长中的作用。这些研究导致了 具有关键信号节点的胰岛素信号网络集成模型的建立 为胰岛素的不同下游作用提供补充信息的差异。这些关键因素 结节还提供可导致胰岛素改变的正负向调节的重要部位 在疾病中采取行动。最近，我们已经开始剖析IR/IGF1R下游的完整磷酸蛋白质组， 通过这一发现，我们发现了两个新的胰岛素/IGF-1信号转录子，FoxK1和FoxK1。 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。 不同组织中的信号网络。我们还开发了iPS细胞模型，专注于细胞的鉴定 人类疾病中胰岛素抵抗的自主成分。事实上，正如我们的初步数据所示， T2D来源的成肌细胞在下游信号和代谢功能方面存在缺陷 体外实验反映了体内发现的缺陷。更重要的是，这些细胞还显示出一种 多维磷酸化网络--在经典的胰岛素信号级联内部和外部。在……里面 这笔拨款，我们将集中于两个相互关联的具体目标：1)阐明胰岛素的根本区别 靶向和全局磷酸蛋白质组学在体外T2D和其他胰岛素抵抗状态中的信号传递 正常人、T2D患者和非糖尿病患者的人iPS细胞来源的成肌细胞 胰岛素抵抗。我们将评估这些变化如何影响细胞功能和参与胰岛素 抵抗。2)确定两个新的下游转录调节因子FoxK1和FoxK1在胰岛素作用中的作用 FoxK2。我们将确定受FoxK1/2调控的基因，确定它们如何补充其他转录 胰岛素调节细胞功能的调节器，以及它们在糖尿病中如何改变。我们还将定义 FoxK调控基因的芯片序列分析最后，我们将创造组织特异性缺失FoxK1的小鼠， FoxK2和选定的组合基因敲除确定它们在胰岛素调节基因中的互补作用 胰岛素在体内的表达和作用。总之，这些研究将使人们对胰岛素的理解达到一个新的水平 糖尿病中的信号及其变化，加深了对胰岛素对基因表达调控的理解 为2型糖尿病等胰岛素抵抗疾病的治疗提供新的切入点。