Depressing Nrip1 Reduces IGF1 Signaling Improves Metabolism and Extends Longevity

抑制 Nrip1 可减少 IGF1 信号传导，改善新陈代谢并延长寿命

• 批准号: 9185250
• 负责人: Rong Yuan
• 金额: $ 13.75万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185250
• 关键词: Adipocytes; Adverse effects; Age; Aging; Alleles; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Area; Award; Biogenesis; Bioinformatics; Biological; Biology of Aging; Body fat; Candidate Disease Gene; Cell Death; Cellular Metabolic Process; Characteristics; Consult; Depressed mood; Development; Diabetes Mellitus; Endocrine Glands; Endocrinology; Energy Metabolism; Ensure; Fatty acid glycerol esters; Female; Foundations; Genes; Genetic; Genetic study; Goals; Growth; High Fat Diet; IGF1 gene; Impairment; Inbred Strain; Inbred Strains Mice; Inflammation; Inflammatory; Intervention; Kidney; Knock-out; Knockout Mice; Knowledge; Learning; Light; Liver; Longevity; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Biology; Mouse Strains; Mus; Muscle; Myocardium; NRIP1 gene; Nuclear Receptors; Obesity; Oxidative Stress; PPAR gamma; Paper; Pathology; Phenotype; Phosphorylation; Physiological; Physiology; Prevention; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Reproduction; Research; Research Personnel; Research Project Grants; Research Technics; Resistance; Role; Sexual Maturation; Signal Transduction; Skeletal Muscle; Solid; Somatotropin; Techniques; Testing; The Jackson Laboratory; Thinness; Time; Tissues; Training; Visceral; Wild Type Mouse; Writing; adipokines; aging gene; base; career; career development; cell growth; cytokine; dietary restriction; experience; genetic analysis; glucose tolerance; improved; insulin sensitivity; metabolic rate; mouse model; mutant; new therapeutic target; notch protein; prevent; protective effect; public health relevance; receptor; skills; success; symposium; therapeutic target; trait; translational medicine; young adult

DESCRIPTION (provided by applicant): In my previous studies, performed in the Jackson Aging Center at the Jackson Laboratory, we used mouse models with a focus on understanding the genetics, physiology and pathology of aging, as well as identifying genetic loci and genes that regulate aging and healthspan. In these studies, we characterized the aging phenotypes of different inbred strains and identified that development traits, such as circulating IGF1 and age of female sexual maturation, are significantly correlated with longevity across the mouse strains. We further verified this correlation by showing that depressing IGF1 by a natural allele could delay female sexual maturation and extend longevity. Using the genetic and bioinformatic methods, we identified a potential aging gene, nuclear receptor interacting protein 1 (Nrip1). We found that the Nrip1 knockout females have a significantly lower level of circulating IGF1 and delayed age of sexual maturation compared with wild-type controls. Other groups have reported that depressing Nrip1 could significantly reduce fat tissue, increase insulin sensitivity and enhance resistance to high-fat diet-induced obesity and diabetes. I am applying the K01 award to support my career development, from identifying candidate genes for aging to investigating the underlying mechanisms. In this study, I will: Aim 1.Characterize the effects of NRIP1 deficiency on metabolism traits and IGF1 signaling in aging. We will test if the protective effects of knocking out Nrip1 could persist through aging. Aim 2. Test the hypothesis that depressing Nrip1 expression in white fat tissue would improve metabolism during aging. Nrip1 null mice are retarded in growth and impaired in female reproduction. To identify a therapeutic target, we will test whether knocking out Nrip1 in white fat tissue would improve metabolism. The tissue-specific knockout of Nrip1 will also provide a valuable model to further understand the role of Nrip1 in the regulations of metabolism and aging. Aim 3. Test the hypothesis that global and white fat tissue-specific reduction of Nrip1 expression would extend longevity. We will compare longevities of Nrip1 null and white fat-specific knockout mice to wild-type controls. To investigat the interaction between Nrip1 and diet restriction, we also will compare longevities for these two mutants to wild-type controls under diet restriction. Nrip1 has wide and complicated effects on regulating metabolisms that relate to many biological mechanisms, including insulin sensitivity, growth hormone/IGF1 signaling, inflammation, mitochondrial function and oxidative stress. These mechanisms have also been suggested as critical to regulating aging. In this project, we propose to use a combination of techniques to study these mechanisms. Thus, if the proposal is awarded, I will not only learn many new research techniques that will significantly enhance my research skills, but I will also study many important aging-related biological mechanisms that are important for building my knowledge of the genetic network of regulating aging. It will also give me a chance to explore the potential therapeutic targets for translational medicine. Importantly, as I continue to build on the solid foundation of genetic aging research from my previous studies, this award will significantly contribute to my long-term goals of revealing the genetic network and molecular mechanisms that regulate aging, as well as identifying novel therapeutic targets for interventions of translational medicine that extend healthspan. To ensure the success of my career development, we have assembled a team of experts in the areas that are proposed to be studied in this proposal. My mentor (Prof. A. Bartke), co-mentor (Prof. H. Van Remmen) and consultants/collaborators (N. Barzilai, J. Kopchick, M. Adamo, M. Parker) have considerable experience in writing and evaluating grant proposals, as well as in researching diverse areas of mammalian endocrinology, metabolism, intracellular signaling and molecular biology pertinent to the biology of aging. We have also developed a complete plan for enhancing my research skills and pushing my career forward, including communicating with my mentor, co-mentor and consultants, training in critical techniques, attending conferences, writing papers and applying new research grants, as well as mentoring younger researchers.

描述（由申请人提供）：在我之前的研究中，在杰克逊实验室的杰克逊衰老中心进行，我们使用小鼠模型，重点了解衰老的遗传学，生理学和病理学，以及识别调节衰老和健康寿命的遗传位点和基因。在这些研究中，我们描述了不同近交系的衰老表型，并确定了发育特征，如循环IGF1和雌性性成熟年龄，与小鼠品系的寿命显著相关。我们进一步证实了这种相关性，通过一个自然等位基因抑制IGF1可以延迟女性性成熟和延长寿命。利用遗传和生物信息学方法，我们发现了一个潜在的衰老基因，核受体相互作用蛋白1 （Nrip1）。我们发现，与野生型对照相比，Nrip1基因敲除的雌性小鼠循环IGF1水平显著降低，性成熟年龄明显延迟。其他研究小组报告说，抑制Nrip1可以显著减少脂肪组织，增加胰岛素敏感性，增强对高脂肪饮食引起的肥胖和糖尿病的抵抗力。我正在申请K01奖来支持我的职业发展，从确定衰老的候选基因到研究潜在的机制。在本研究中，我将：目标1。表征NRIP1缺乏对衰老过程中代谢特性和IGF1信号传导的影响。我们将测试其保护效果