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: 8617002
• 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/8617002
• 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; Characteristics; Consult; Depressed mood; Development; Diabetes Mellitus; Diet; Endocrine Glands; Endocrinology; Energy Metabolism; Ensure; Fatty acid glycerol esters; Female; Foundations; Genes; Genetic; Goals; Growth; Health; IGF1 gene; 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; Time; Tissues; Training; Visceral; Wild Type Mouse; Writing; age related; aging gene; base; career; career development; cell growth; cytokine; dietary restriction; experience; genetic analysis; glucose tolerance; human NRIP1 protein; improved; insulin sensitivity; mouse model; mutant; new therapeutic target; notch protein; prevent; protective effect; 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）：在我之前在杰克逊实验室的杰克逊衰老中心进行的研究中，我们使用小鼠模型，重点是了解衰老的遗传学、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小鼠的衰老表型，并发现循环 IGF1 和雌性性成熟年龄等发育特征与小鼠品系的寿命显着相关。我们通过证明天然等位基因抑制 IGF1 可以延迟女性性成熟并延长寿命，进一步验证了这种相关性。利用遗传学和生物信息学方法，我们鉴定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 敲除雌性的循环 IGF1 水平显着降低，并且性成熟年龄延迟。其他研究小组报告称，抑制 Nrip1 可以显着减少脂肪组织，增加胰岛素敏感性，并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，从识别衰老的候选基因到研究潜在的机制。在这项研究中，我将： 目标 1. 表征 NRIP1 缺乏对衰老过程中代谢特征和 IGF1 信号传导的影响。我们将测试是否有保护作用 敲除 Nrip1 的效果可能会随着衰老而持续存在。目标 2. 检验以下假设：抑制白色脂肪组织中的 Nrip1 表达会改善衰老过程中的新陈代谢。 Nrip1 缺失小鼠生长迟缓，雌性生殖能力受损。为了确定治疗靶点，我们将测试敲除白色脂肪组织中的 Nrip1 是否会改善新陈代谢。 Nrip1的组织特异性敲除也将为进一步了解Nrip1在代谢和衰老调节中的作用提供有价值的模型。目标 3. 检验以下假设：整体和白色脂肪组织特异性减少 Nrip1 表达会延长寿命。我们将比较 Nrip1 缺失小鼠和白色脂肪特异性敲除小鼠与野生型对照小鼠的寿命。为了研究 Nrip1 和饮食限制之间的相互作用，我们还将比较这两种突变体与野生型对照在饮食限制下的寿命。 Nrip1 对调节代谢具有广泛而复杂的影响，这些影响与许多生物机制相关，包括胰岛素敏感性、生长激素/IGF1 信号传导、炎症、线粒体功能和氧化应激。这些机制也被认为对于调节衰老至关重要。在这个项目中，我们建议使用多种技术的组合来研究这些机制。因此，如果该提案获得批准，我不仅将学习许多新的研究技术，这将显着提高我的研究技能，而且我还将研究许多与衰老相关的重要生物机制，这些机制对于建立我对调节衰老的遗传网络的了解非常重要。它还将使我有机会探索转化医学的潜在治疗靶点。重要的是，随着我继续在之前的研究中建立遗传衰老研究的坚实基础，该奖项将极大地有助于我的长期目标，即揭示调节衰老的遗传网络和分子机制，以及为延长健康寿命的转化医学干预确定新的治疗靶点。为了确保我职业发展的成功，我们在本提案中建议研究的领域组建了一个专家团队。我的导师（A. Bartke 教授）、共同导师（H. Van Remmen 教授）和顾问/合作者（N. Barzilai、J. Kopchick、M. Adamo、M. Parker）在撰写和评估资助提案以及研究与衰老生物学相关的哺乳动物内分泌学、新陈代谢、细胞内信号传导和分子生物学等多个领域方面拥有丰富的经验。我们还制定了一个完整的计划来提高我的研究技能并推动我的职业发展，包括与我的导师、共同导师和顾问沟通、关键技术培训、参加会议、撰写论文和申请新的研究资助，以及指导年轻的研究人员。