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The metabolomic consequences of small size and long life

小尺寸和长寿命的代谢组学后果

基本信息

批准号：
10362125
负责人：
Jessica Marie Hoffman
金额：
$ 9.96万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

项目摘要

Project Summary This research proposal has been developed to equip the candidate, Dr. Jessica Hoffman, with the experience, skills, and tools needed to successfully transition into a faculty position at a large public research university. The proposed research will discover novel metabolic mechanisms that lead to small size and long life across natural genetic variation and lifespan extending interventions with a specific focus on the degradation of tryptophan to kynurenine. Dr. Hoffman will receive extensive training in mouse husbandry techniques, molecular biology, and metabolomics data acquisition and analysis under the guidance of her mentorship team, Drs. Steven Austad, Stephen Barnes, and Liou Sun, all at the University of Alabama at Birmingham and active members of UAB's Nathan Shock Center for Excellence in the Biology of Aging. Preliminary studies completed under the direction of Dr. Steven Austad indicate size plays a large role in explaining the variation in metabolomic profiles within a species (companion dogs) that show a negative correlation between body size and longevity. And work with Dr. Sun suggests that metabolomic profiles are different between small, long-lived growth hormone (GH) disrupted mice and wild type mice. One pathway found to be similar between the two species is the breakdown of tryptophan to kynurenine. In both small dogs and small GH disrupted mice kynurenine levels are higher and tryptophan levels are lower than their larger counterparts. This suggests that the degradation of tryptophan to kynurenine may be influencing the longevity extension seen in small individuals of a species. The overall goal of this project is to expand our knowledge of small size and long life and to further tease apart the molecular mechanisms that underlie the size longevity tradeoff seen across species. The overarching hypothesis is that tryptophan metabolic dysregulation is partially modulated by GH and energy intake and provides an IGF- I independent mechanisms of long-life and small body size across species. This hypothesis will be addressed by three specific aims, each of which will help develop Dr. Hoffman as an independent investigator. 1) Determine the dynamics of tryptophan metabolism to the longevity effect of reduced GH activity. 2) Determine how metabolomic profiles, specifically tryptophan degradation metabolism varies across different interventions that show smaller size and longer life across species. 3) Determine lifespan consequences of genetic manipulation of tryptophan metabolism genes in fruit flies. Overall, this proposal will increase our knowledge on the molecular underpinnings that lead to variation in body size and lifespan and will provide new hypotheses about potential interventions to improve lifespan and healthspan.

项目摘要这项研究提案是为了让候选人杰西卡·霍夫曼博士具备以下经验：成功过渡到大型公立研究型大学教职所需的技能和工具。这个拟议中的研究将发现新的新陈代谢机制，这些机制会导致体型较小，寿命较长的天然遗传变异和延长寿命的干预措施，特别关注色氨酸的降解犬尿氨酸。霍夫曼博士将接受广泛的老鼠饲养技术、分子生物学和在她的导师团队Steven Austad博士的指导下，获得和分析代谢组学数据， Stephen Barnes和Liou Sun，他们都在阿拉巴马大学伯明翰分校工作，都是UAB的活跃成员内森·肖克衰老生物学卓越中心。在指导下完成的初步研究史蒂文·奥斯塔德博士的研究表明，大小在解释一个人的代谢谱变化中起着很大的作用身体大小与寿命呈负相关的品种(伴犬)。并与Dr. Sun认为，在小的、长寿的生长激素(GH)被干扰之间，代谢谱是不同的小鼠和野生型小鼠。在这两个物种之间发现的一个相似的途径是从色氨酸到犬尿氨酸。在小狗和小GH干扰的小鼠中，犬尿氨酸水平较高，色氨酸水平低于体型较大的同类产品。这表明色氨酸的降解为犬尿氨酸可能正在影响一个物种的小个体的寿命延长。的总目标是这个项目是为了扩大我们对小尺寸和长寿命的知识，并进一步梳理分子不同物种之间体型长寿权衡的机制。最重要的假设是色氨酸代谢失调部分受生长激素和能量摄入的调节，并提供IGF- I跨物种的长寿和小体型的独立机制。这一假设将是有三个具体的目标，每个目标都有助于将霍夫曼博士培养成一名独立的调查员。 1)测定色氨酸代谢动力学对生长激素活性降低对长寿的影响。2)确定代谢组谱，特别是色氨酸降解代谢在不同干预措施中的差异它们显示出较小的体型和较长的跨物种寿命。3)确定遗传后果的寿命果蝇色氨酸代谢基因的调控。总体而言，这项建议将增加我们对导致身体大小和寿命变化的分子基础，并将提供新的假设关于延长寿命和健康寿命的潜在干预措施。