Functional Characterization and Physiological Consequences of Human Longevity-Associated IGF1R Variants

人类长寿相关 IGF1R 变异体的功能特征和生理后果

• 批准号: 9062284
• 负责人: Simon C Johnson
• 金额: $ 1.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062284
• 关键词: Address; Affect; Aging; Aging-Related Process; Animal Model; Attenuated; Behavioral; Biochemical; Biological; Biological Assay; Caring; Cell Aging; Cell Culture Techniques; Cell Cycle Progression; Cell model; Cells; Centenarian; Chronic Disease; Data; Development; Dimerization; Disease; Elderly; Embryo; Eukaryota; Fibroblasts; Future; Gene Mutation; Genes; Genetic; Genetic Variation; Goals; Growth; Health; Health Care Costs; High Fat Diet; Human; Insulin; Insulin-Like Growth Factor I; Intervention; Invertebrates; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Life; Ligands; Longevity; Lymphocyte; Mammals; Membrane; Metabolic Diseases; Metabolic stress; Metabolism; Missense Mutation; Modeling; Modification; Molecular; Mus; Mutation; Nematoda; Nutrient; Organism; Pathway interactions; Pharmacologic Substance; Physical activity; Physiological; Physiology; Prevention; Process; Public Health; Receptor Gene; Research; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Variant; age related; attenuation; base; biological adaptation to stress; cell age; cellular engineering; disorder risk; fly; gene function; genetic approach; genetic variant; healthy aging; in vivo; insight; insulin signaling; mouse model; novel strategies; novel therapeutics; prevent; protein function; protein protein interaction; public health relevance; receptor; receptor binding; response; therapeutic development; translational approach

 DESCRIPTION (provided by applicant): While there is overwhelming evidence that reduced insulin/insulin like growth factor-1 (IGF1) signaling (IIS) extends lifespan in invertebrate and murine models, the impact of this evolutionarily conserved pathway on human longevity remains unclear. Research in the Suh lab has led to the discovery of two centenarian- enriched missense mutations in the IGF-1 receptor gene (IGF1R), A37T (M1) and R407H (M2), associated with decreased IIS in lymphocytes established from carriers as compared to non-carriers (Suh et al., PNAS, 2008). The M1 and M2 variants were shown to cause attenuation of IGF1 signaling, reduced expression of IGF1-activated genes, and delayed cell cycle progression relative to wild-type human IGF1R when expressed in Igf1r null mouse embryonic fibroblasts (Tazearslan et al., Aging Cell, 2011). While the association of IIS with longevity is known, the specific role of IIS in regulating human lifespan, including how missense mutations in IIS components modify survival and disease risk, is not known. The goal of this proposal is to elucidate the molecular and physiological mechanisms of longevity promotion by missense mutations in the IGF-1 receptor using cells expressing centenarian enriched variant receptor and mice carrying a knock-in of a centenarian associated variant. The IGF-1 receptor has been studied in mice in respect to aging but only in the context of knockout, or heterozygous deficiency. The IGF-1 receptor has multiple roles in regulating cellular and organism physiology including non-receptor functions and modification of other membrane bound receptors through dimerization. In addition, stimulation of the IGF-1 receptor activates multiple distinct intracelluar signaling cascades through specific ligand-receptor interactions and our preliminary data shows that centenarian associated mutations in IGF-1 receptor differentially affect these downstream signaling pathways in a tissue specific manner. In order to address this goal we will (1) examine IGF1R variant processing, assembly, protein-protein interaction, and impact on signaling in cell based assays; (2) define the effects of a centenarian associated IGF1R variant on growth, metabolism, and in vivo insulin/IGF-1 signaling in mice using the knock-in model we have produced; (3) determine the impact of the centenarian associated IGF1R variant on the response to high- fat diet, a model for age-related metabolic disease. We hypothesize that centenarian associated IGF1R variants have functionally relevant effects on cellular and organism physiology resulting from changes to protein function. We further hypothesize that these effects will be partly functionally distinct from simply reducing levels of IGF-1 receptor, including differential effects on downstream signaling and non-receptor functions of IGF1R. Lastly, we predict that these molecular changes and cellular effects will lead to beneficial systemic functional changes in the mouse knock-in model that underlie the association to human longevity, including resistance to metabolic stress in the high-fat diet paradigm. Understanding the physiological role of naturally occurring centenarian associated IGF1R genetic variation will pave the way for future development of therapeutic strategies for preventing and treating age-related disease based on the molecular mechanisms we describe.

 描述（由适用提供）：虽然有大量证据表明，胰岛素1（IGF1）信号（IIS）降低了胰岛素/胰岛素（IIS），延长了无脊椎动物和鼠模型的寿命，但这种进化途径对人寿命的影响仍然不清楚。 SUH实验室中的研究导致发现了在IGF-1受体基因（IGF1R），A37T（M1）和R407H（M2）中发现了两个富含百年的错义突变，与与非驾驶员相比，与载体建立的淋巴细胞中的IIS相关（SUH等人（Suh et et al.，pnas，2008年）。显示M1和M2变体可导致IGF1信号传导的衰减，IGF1激活基因的表达降低以及相对于野生型人类IGF1R的延迟细胞周期进展，当时IGF1R Null Null Null小鼠胚胎型成纤维细胞表达（Tazearslan等人（Tazearslan等）（Tazearslan et allasts）。尽管IIS与寿命的关联是已知的，但IIS在确定人类寿命中的具体作用，包括IIS组件中的错义突变如何改变生存和疾病风险。该提案的目的是使用表达一百年富集的变体受体和带有一百岁式相关变体的敲击的小鼠的细胞来阐明IGF-1受体中的寿命促进的分子和物理机制。 IGF-1受体在衰老方面已经在小鼠中进行了研究，但仅在敲除或杂合缺乏症的背景下进行了研究。 IGF-1受体在控制细胞和生物体生理学中具有多个作用，包括非受体功能以及通过二聚化修饰其他膜结合受体。此外，IGF-1受体的刺激通过特定的配体 - 受体相互作用激活了多个不同的ellaceluar信号传导级联反应，我们的初步数据表明，IGF-1受体中的百年相关突变在组织特定方式中对这些下游信号途径的影响不同。为了解决此目标，我们将（1）检查IGF1R变体处理，组装，蛋白质 - 蛋白质相互作用以及对基于细胞测定的信号的影响； （2）使用我们产生的敲入模型来定义一百年相关的IGF1R变体对小鼠生长，代谢和体内胰岛素/IGF-1信号传导的影响； （3）确定一百年相关的IGF1R变体对高脂饮食反应的影响，这是与年龄相关的代谢疾病的模型。我们假设一百年相关的IGF1R变体对蛋白质功能变化导致的细胞和生物体生理具有功能相关的影响。我们进一步假设这些效应将在功能上与简单地降低IGF-1受体的水平有所不同，包括对IGF1R下游信号传导和非受体功能的差异影响。最后，我们预测，这些分子变化和细胞效应将导致小鼠敲入模型中有益的全身功能变化，这是与人类长寿相关的基础，包括在高脂饮食范式中对代谢应激的抗性。了解自然发生的一百年相关的IGF1R遗传变异的身体作用将为未来开发理论策略的发展铺平道路，以根据我们描述的分子机制来预防和治疗与年龄相关的疾病。