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: 8774568
• 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/8774568
• 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; Genetic study; 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; metabolic rate; 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）：在我以前的研究中，在杰克逊实验室的杰克逊老化中心进行，我们使用了小鼠模型，重点是了解衰老的遗传学，生理和病理学，并鉴定了调节衰老和健康范围的遗传基因座和基因。在这些研究中，我们表征了不同近交菌株的衰老表型，并确定发育特征（例如循环IGF1和女性性成熟年龄）与整个小鼠菌株的寿命显着相关。我们通过表明自然等位基因压抑IGF1的抑制可能会延迟女性性成熟并延长寿命，从而进一步验证了这种相关性。使用遗传和生物信息学方法，我们确定了潜在的衰老基因，即核受体相互作用蛋白1（NRIP1）。我们发现，与野生型对照相比，NRIP1敲除女性的循环IGF1水平明显较低，性成熟年龄延迟。其他小组报告说，抑制NRIP1可以显着降低脂肪组织，提高胰岛素敏感性并增强对高脂饮食诱导的肥胖症和糖尿病的耐药性。 我正在应用K01奖，以支持我的职业发展，从确定老化的候选基因到研究基本机制。在这项研究中，我将：目标1.将NRIP1缺乏症对新陈代谢特征和IGF1信号传导的影响征兆。我们将测试保护作用是否 淘汰NRIP1可以通过衰老持续存在。 AIM 2。检验以下假设：白脂肪组织中NRIP1表达降低将改善衰老期间的新陈代谢。 NRIP1无效小鼠在生长中受阻，并在女性繁殖中受损。为了确定治疗靶标，我们将测试在白脂肪组织中敲除NRIP1是否会改善新陈代谢。 NRIP1的组织特异性敲除还将提供一个有价值的模型，以进一步了解NRIP1在代谢和衰老法规中的作用。 AIM 3。检验以下假设：NRIP1表达的全球和白脂肪组织特异性降低将延长寿命。我们将比较NRIP1 NULL和白脂肪特异性敲除小鼠的寿命与野生型对照。为了研究NRIP1与饮食限制之间的相互作用，我们还将在饮食限制下将这两个突变体的寿命与野生型对照进行比较。 NRIP1对调节与许多生物学机制有关的代谢具有广泛而复杂的影响，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调节衰老至关重要。在这个项目中，我们建议使用多种技术来研究这些机制。因此，如果授予该提案，我不仅会学到许多新的研究技术，这些新研究技术会大大提高我的研究技能，而且我还将研究许多与衰老相关的重要生物学机制，这些机制对于建立我对调节衰老的遗传网络的了解很重要。这也将使我有机会探索转化医学的潜在治疗靶标。重要的是，随着我继续从以前的研究中基于遗传性衰老研究的稳固基础，该奖项将极大地促进我的长期目标，即揭示调节衰老的遗传网络和分子机制，并确定新颖的治疗靶标，以扩展健康范围的转化医学干预措施。 为了确保我的职业发展取得成功，我们组建了一个专家团队，该团队在该提案中建议研究的领域。我的导师（A. Bartke教授），同事（H. van Remmen教授）和顾问/合作者（N. Barzilai，J。Kopchick，M。Adamo，M。Parker）在写作和评估赠款建议方面具有丰富的经验，对哺乳动物内分泌学的多元化社会学研究和分子学的多元化领域以及分子学的多元化领域以及在研究中的多元化领域。我们还制定了一个完整的计划，以提高我的研究技能并推动我的职业发展，包括与我的导师，联合学和顾问交流，关键技术培训，参加会议，写论文和应用新的研究赠款以及指导年轻的研究人员。