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: 10665775
• 负责人: C RONALD KAHN
• 金额: $ 58.94万
• 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/10665775
• 关键词: Affect; Applications Grants; Attention; Cell Nucleus; Cell model; Cell physiology; Cells; ChIP-seq; Complement; Coupling; Data; Defect; Development; Diabetes Mellitus; Diet; Dimensions; Disease; Environmental Risk Factor; Exclusion; FOXO1A gene; FRAP1 gene; Fatty acid glycerol esters; 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; Link; Liver; MAPK8 gene; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Molecular Profiling; Mouse Strains; Mus; Muscle; Myoblasts; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; PIK3CG gene; 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： 这是一个修订的赠款申请，名为“糖尿病后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）作用以产生较宽 代谢和生长对体内大多数细胞的影响范围。多年来，我实验室的工作一直是 致力于了解此过程中的中间信号以及如何改变疾病。 这，我们已经广泛表征了胰岛素受体底物蛋白在耦合IR和 IGF1R到下游效应系统，PI-3激酶和AKT在代谢作用中的重要作用 胰岛素和MAP/MTOR/S6K激酶途径在生长促进中的影响。这些研究导致了 开发胰岛素信号网络的集成模型，其中有信号的关键节点 分歧为胰岛素的不同下游动作提供完整的信息。这些关键 节点还提供了阳性和阴性调节的重要部位，可以导致胰岛素的改变 疾病的作用。最近，我们开始剖析下游IR/IGF1R的全磷蛋白质组，并剖析 通过此，已经确定了胰岛素/IGF-1信号传导的两个新的叉状转录介质，FOXK1和 foxk2。从疾病的角度来看，我们还展示了不同的胰岛素耐药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细胞模型以专注于识别细胞 人类疾病中胰岛素抵抗的自主成分。确实，如我们的初步数据所示， 源自T2D IPSC的肌细胞在下游信号传导和代谢功能中表现出缺陷 体外反映体内发现的缺陷。更重要的是，这些细胞还显示了A的失调 多维磷酸化网络 - 在经典胰岛素信号级联内部和外部。 这笔赠款，我们将重点关注两个相互关联的特定目的：1）阐明胰岛素的基本差异 使用靶向和全球磷酸蛋白质组学在T2D和其他胰岛素耐药状态下的信号传导 来自正常人，T2D患者和非糖尿病患者的人IPS细胞衍生的肌细胞 胰岛素抵抗。我们将评估这些变化如何影响细胞功能并参与胰岛素 反抗。 2）定义两个新的下游转录调节剂在胰岛素作用中的作用，FOXK1和 foxk2。我们将确定FOXK1/2调节的基因，确定它们如何补充其他转录 细胞功能调节胰岛素调节的调节剂，以及如何改变糖尿病。我们还将定义 Foxk使用芯片序列调节基因。最后，我们将创建带有组织特异性缺失Foxk1的小鼠， FOXK2和选定的组合敲除，以定义其在胰岛素调节基因中的完整作用 体内表达和胰岛素作用。这些研究一起将导致新的理解胰岛素 信号传导及其在糖尿病中的改变，提供对基因表达胰岛素调节的更深入的了解 并为2型糖尿病和其他胰岛素耐药性疾病的治疗提供了新的观点。