Depressing Nrip1 Reduces IGF1 Signaling Improves Metabolism and Extends Longevity

描述(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的研究中，我们使用了小鼠模型，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，我们对不同近交系的衰老表型进行了表征，并确定了发育特征，如循环IGF1和雌性性成熟的年龄，与小鼠品系之间的寿命显著相关。我们进一步验证了这种相关性，表明通过自然等位基因抑制IGF1可以延缓女性的性成熟和延长寿命。利用遗传学和生物信息学的方法，我们发现了一个潜在的衰老基因--核受体相互作用蛋白1(Nrig1)。我们发现，与野生型对照相比，Nrig1基因敲除的雌性动物循环中IGF1水平显著降低，性成熟年龄延迟。其他研究小组报告称，抑制Nrig1可以显著减少脂肪组织，提高胰岛素敏感性，并增强对高脂饮食导致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，从识别导致衰老的候选基因到研究其潜在的机制。在本研究中，我将：目的：1.研究NRIP1缺乏对衰老过程中代谢特征和IGF1信号转导的影响。我们将测试是否有保护效果 敲除Nrig1的可能性可能会持续到衰老。目的2.验证抑制白色脂肪组织中Nrig1表达可改善衰老过程中新陈代谢的假设。Nrig1基因缺失的小鼠生长迟缓，雌性生殖受损。为了确定治疗靶点，我们将测试敲除白色脂肪组织中的Nrig1是否会改善新陈代谢。组织特异性的Nrig1基因敲除也将为进一步了解Nrig1在新陈代谢和衰老调节中的作用提供一个有价值的模型。目的3.验证假设，即全局和白色脂肪组织特异性降低Nrig1的表达将延长寿命。我们将比较Nrig1基因缺失和白色脂肪特异性基因敲除小鼠与野生型对照小鼠的寿命。为了研究Nrig1与饮食限制之间的相互作用，我们还将这两个突变体的寿命与饮食限制下的野生型对照进行比较。Nrig1在调节代谢方面具有广泛而复杂的作用，涉及许多生物学机制，包括胰岛素敏感性、生长激素/IGF1信号转导、炎症、线粒体功能和氧化应激。这些机制也被认为是调节衰老的关键。在这个项目中，我们建议使用组合技术来研究这些机制。因此，如果提案获奖，我不仅将学习许多新的研究技术，这些技术将显著提高我的研究技能，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知识非常重要。这也让我有机会探索转化医学的潜在治疗靶点。重要的是，随着我继续建立在我之前研究的遗传衰老研究的坚实基础上，这个奖项将大大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。为了确保我的职业发展取得成功，我们组建了一个专家小组，负责本提案中拟研究的领域。我的导师(A.Bartke教授)、共同导师(H.Van Remman教授)和顾问/合作者(N.Barzilai、J.Kopchick、M.Adamo、M.Parker)在撰写和评估赠款提案以及研究哺乳动物内分泌学、新陈代谢、细胞内信号和与衰老生物学相关的分子生物学方面都有相当丰富的经验。我们还制定了一套完整的计划，以提高我的研究技能，推动我的事业向前发展，包括与我的导师、合作导师和顾问沟通，培训关键技术，参加会议，撰写论文和申请新的研究拨款，以及指导年轻的研究人员。

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.