The metabolomic consequences of small size and long life

小尺寸和长寿命的代谢组学后果

• 批准号: 9902281
• 负责人: Jessica Marie Hoffman
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902281
• 关键词: Address; Affect; Age; Aging; Alabama; Animal Model; Animals; Biological Process; Biology of Aging; Body Size; Callithrix; Calories; Canis familiaris; Companions; Complex; Data Analyses; Diet; Dioxygenases; Down-Regulation; Drosophila genus; Energy Intake; Enzymes; Essential Amino Acids; Faculty; Female; Future; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Human; Individual; Insulin; Insulin-Like Growth Factor I; Intervention; Knowledge; Kynurenine; Lead; Life; Longevity; Measures; Melatonin; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methionine; Molecular; Molecular Biology; Mus; Nerve Degeneration; Neurohormones; Nutrient; Pathway interactions; Pattern; Phase; Phenotype; Play; Positioning Attribute; Process; Production; Protein Biosynthesis; Research; Research Personnel; Research Project Summaries; Research Proposals; Role; Route; Serotonin; Shock; Signal Transduction; Sirolimus; Somatotropin; Techniques; The Sun; Training; Translating; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Universities; Variant; Wild Type Mouse; Work; age effect; data acquisition; dietary manipulation; experience; experimental study; fly; genetic manipulation; healthspan; hormonal signals; improved; indoleamine; insulin signaling; member; metabolome; metabolomics; mouse model; novel; skills; tool

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 这项研究建议是为候选人杰西卡·霍夫曼（Jessica Hoffman）提供的经验而制定的 在大型公共研究大学中成功过渡到教职员工所需的技能和工具。这 拟议的研究将发现新型的代谢机制，这些机制会导致自然的尺寸和长寿 遗传变异和寿命延长干预措施，特别关注色氨酸的降解为 Kynurenine。霍夫曼博士将接受大量的鼠标饲养技术，分子生物学和 在她的指导团队的指导下，代谢组学数据获取和分析Drs。史蒂文·奥斯塔德（Steven Austad）， 斯蒂芬·巴恩斯（Stephen Barnes）和洛乌·孙 内森（Nathan）衰老生物学卓越中心。初步研究在指导下完成 史蒂文·奥斯塔德（Steven Austad 物种（伴侣犬）在体型和寿命之间显示出负相关。并与博士合作 太阳表明，小型，长寿命的生长激素（GH）中断的代谢组谱是不同的 小鼠和野生型小鼠。两种物种之间发现的一条途径是分解 色氨酸到kynurenine。在小狗和小的GH中断的小鼠中，kynurenine水平都更高，并且 色氨酸水平低于较大的对应物。这表明色氨酸降解为 Kynurenine可能会影响物种小个体中看到的寿命延长。总体目标 该项目是为了扩大我们对小规模和长寿的了解，并进一步取笑分子 在物种之间看到的寿命折衷的机制。总体假设是 色氨酸代谢失调部分由GH和能量摄入部分调节，并提供IGF- I独立的长寿机制和各种物种的体型小。这个假设将是 由三个特定目标解决，每个目标都将有助于发展霍夫曼博士为独立调查员。 1）确定色氨酸代谢的动力学对降低GH活性的寿命效应。 2）确定 代谢组曲线（特别是色氨酸降解代谢）如何在不同的干预措施中变化 这显示了各种物种的尺寸较小和更长的寿命。 3）确定遗传的寿命后果 在果蝇中操纵色氨酸代谢基因。总体而言，该建议将增加我们的知识 导致体型和寿命变化的分子基础，并将提供新的假设 关于改善寿命和健康状况的潜在干预措施。