Role of IGF-1 and insulin receptors beta-cell survival

IGF-1 和胰岛素受体 β 细胞存活的作用

基本信息

批准号：
8929208
负责人：
ROHIT N. KULKARNI
金额：
$ 41.38万
依托单位：
JOSLIN DIABETES CENTER
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：
2004-03-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8929208
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Acetylation Achievement Address Beta Cell Biology Boxing Candidate Disease Gene Cell Line Cell Nucleus Cell Survival Cell membrane Cell physiology Cells Cellular biology ChIP-seq Cytoplasm DNA Methylation Data Diabetes Mellitus Disease Drug Targeting Enzymes Epigenetic Process Family Functional disorder Funding Gene Expression Gene Targeting Generations Genes Genetic Genomics Goals Grant Growth Growth Factor Health Histone Acetylation Homeodomain Proteins Homeostasis Human Human Cell Line IGF1 gene In Vitro Insulin Insulin Receptor Insulin Resistance Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Knock-in Mouse Knock-out Laboratories Ligands Link Malignant Neoplasms Mammalian Cell Manuscripts Mediating Metabolic Metabolic Diseases Mus Mutant Strains Mice Nature Nuclear Nuclear Localization Signal Obesity Pancreas Paper Pathway interactions Peptide Initiation Factors Phenotype Phosphotransferases Physiological Process Proteins Proto-Oncogenes Protocols documentation Publishing RNA-Binding Proteins Reagent Regulation Reporting Research Role Sequence Analysis Serine Signal Pathway Signal Transduction Signaling Protein Site Stimulus Therapeutic Threonine Time Tissues Transgenic Mice Translating Translations Tuberous sclerosis protein complex United States National Institutes of Health Work base biological adaptation to stress carboxypeptidase H cell growth cell type chromatin immunoprecipitation cost endoplasmic reticulum stress epigenetic regulation follow-up genome-wide in vivo innovation insight islet mouse model mutant new therapeutic target novel programs prohormone receptor receptor binding response stem transcription factor type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): After decades of research efforts and billions of dollars in cost, diabetes and obesity still stand as major health challenges in the developed and developing worlds. The elusive nature of the metabolic disorders stems largely from incomplete understanding of the growth factor signaling pathways that regulate cellular homeostasis in different metabolic cell types. Two long-standing questions include: 1) How do cell membrane bound receptors directly mediate their effects on gene expression in the nucleus thereby regulating a cell's response to a metabolic challenge and 2) Whether insulin receptor (IR) and insulin-like growth factor-1 receptors (IGF1R) that activate common downstream proteins in their signaling pathways, have specific and distinct gene targets that would be suitable for novel drug targets for each receptor. Our work presents the novel evidence that IR and IGF1R, classic cell membrane bound receptors, show ligand-dependent translocation to the nucleus of mouse and human cells. Our genome-wide chromatin immunoprecipitation (ChIP) sequencing analyses provides compelling evidence for the direct recruitment of IR and IGF1R to genomic sites, unfolding a novel paradigm that has the potential to address critical scientific questions imperative to therapeutic innovation, that have remained largely unexplored. We believe our findings have the exciting potential to: a) better understand how signals initiated at the cell membrane are translated into a response to regulate gene expression in the nucleus, b) delineate the differences in IR and IGF1R actions and their response to growth factor stimuli to regulate metabolic function, and c) identify novel players and mechanisms of growth factor signaling that impact both the genetic and epigenetic mechanisms across several metabolic tissues, and hence have broad implications for the treatment of metabolic diseases and cancer.

描述（由适用提供）：经过数十年的研究工作以及数十亿美元的成本，糖尿病和肥胖仍然是发达国家和发展中国家的主要健康挑战。代谢性疾病的难以捉摸的性质很大程度上是由于对调节不同代谢细胞类型中细胞稳态的生长因子信号传导途径的不完全理解。两个长期存在的问题包括：1）细胞膜结合受体如何直接介导其对核中基因表达的影响，从而调节细胞对代谢挑战的反应以及2）2）2）是否是否是否是否能激活每个人的靶标，并且可以适用于基因的靶标，并且是否会激活常见的下游蛋白，以适用于基因的靶向，并且是适合于基因的靶标。我们的工作提出了一个新的证据，即经典细胞膜结合的接收器IR和IGF1R显示了配体依赖性易位到小鼠和人类细胞的核心。我们全基因组染色质免疫沉淀（CHIP）测序分析为直接募集IR和IGF1R直接募集到基因组部位提供了令人信服的证据，展现了一种新的范式，该范式有可能解决对治疗创新的关键科学问题的潜力，这些范式在很大程度上出乎意料。 We believe our findings have the exciting potential to: a) better understand how signals initiated at the cell membrane are translated into a response to regulate gene expression in the nucleus, b) delineate the differences in IR and IGF1R actions and their response to growth factor stimuli to regulate metabolic function, and c) identify novel players and mechanisms of growth factor signaling that impact both the genetic and epigenetic mechanisms across several metabolic tissues, and因此，对代谢疾病和癌症的治疗具有广泛的影响。