Discover determinants of individual longevity and health in C. elegans

发现线虫个体寿命和健康的决定因素

• 批准号: 8785150
• 负责人: Zachary Pincus
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785150
• 关键词: Adult; Aging; Algorithms; Animals; Area; Award; Biochemistry; Biological Assay; Biological Markers; Biology; Biology of Aging; Buffers; Caenorhabditis; Caenorhabditis elegans; Candidate Disease Gene; Cell Shape; Cells; Cellular biology; Cessation of life; Chromatin Structure; Communities; Complex; Computing Methodologies; DNA Modification Process; Development; Development Plans; Developmental Biology; Developmental Process; Diagnostic; Disease; Environment; Epigenetic Process; Faculty; Future; Gene Expression; Generic Drugs; Genes; Genetic; Goals; Graduate Degree; Health; Human; Image Analysis; Inbreeding; Individual; Individual Differences; Instruction; Insulin; Insulin-Like Growth Factor I; Intervention; Investigation; Lead; Life; Life Stress; Literature; Longevity; Longevity Pathway; Measurable; Measures; Mentors; Methodology; Methods; MicroRNAs; Mining; Molecular; Molecular Biology; Motion; Nematoda; Noise; Pathway interactions; Physiological; Physiological Processes; Population; Populations at Risk; Postdoctoral Fellow; Process; Reporter; Reporter Genes; Research; Research Personnel; Resistance; Shapes; Signal Transduction; Societies; Source; Stereotyping; Stress; System; Testing; Time; Training; Universities; Work; acute stress; anti aging; biological adaptation to stress; biomedical informatics; career development; cell motility; cohort; combat; high risk; insulin signaling; life history; light microscopy; mathematical analysis; member; method development; minimally invasive; non-genetic; novel; research study; senescence; stressor; tool

The proposed work explores genetic and physiological factors that determine inter-individual differences in lifespan, using genetically identical C. elegans reared in a novel system that allows individuals to be followed throughout their lives in isolated, identical environments. Preliminary research using this method identified a microRNA regulator of insulin/IGF-1-like signaling that can, early in adult life, predict almost half of later lifespan variability. This "Pathway to Independence" award application includes a mentored career development plan for transition of the candidate, Dr. Zach Pincus, into an independent investigator, as well an accompanying research plan describing the proposed experiments on the determinants of individual lifespan, health, and stress-resistance. The candidate, Dr. Pincus, is a postdoctoral fellow at Yale, in the lab of Dr. Frank Slack in the Department of Molecular, Cellular, and Developmental Biology. The work leading to his graduate degree in Biomedical Informatics at Stanford University was conducted in the lab of Dr. Julie Theriot in the Stanford Biochemistry Department, and focused on algorithms for representing and comparing the shapes of populations of single cells. In the Theriot lab, Dr. Pincus then applied these tools to biophysical studies on the molecular determinants of complex and largescale organization such as cell shape and movement. The mentoring and career development plan will supplement his background, which is evenly split between bench biology and computational methods development, with training and instruction in each, and in the particular areas that this project involves: aging biology, nematode biology, mathematical analysis of dynamical systems, and light microscopy. Dr. Pincus's goal is to become a faculty member in an interdisciplinary bioscience, developmental biology, or similar department at an academic, private, or governmental facility, in which he can research the biology of inter-individual variability and how it relates to lifespan determination. This research on inter-individual variability requires a novel assay system developed by Dr. Pincus that allows individual C. elegans to be examined by light microscopy throughout their lives. The project proposes to measure early-life levels of various fluorescent reporters of relevant physiological processes including insulin signaling, developmental robustness, and stress responses, and to determine which if any of those processes determine later longevity and health. The project further proposes to determine, by several independent avenues of investigation, whether there are distinct long-lived, stress- resistant "robust" cohorts of animals, distinct from more "frail" individuals, as has long been proposed in the literature. This work has clear and significant implications for human health and longevity. The identification of biomarkers that predict or determine future stress-resistance, robustness, and longevity, which are currently extremely rare, will be of great value to an aging society as such markers may lead to the development of appropriate lifespan-prolonging interventions and the ability to target them to at-risk populations.

拟议的工作探讨了决定个体间的遗传和生理因素 寿命的差异，使用在一个新的系统中饲养的基因相同的线虫，该系统允许个体 他们的一生都在孤立的、相同的环境中被跟踪。使用该方法的初步研究 发现了一种胰岛素/IGF-1样信号转导的 microRNA 调节因子，可以在成年早期预测近一半的 以后的寿命变化。此“独立之路”奖项申请包括受指导的职业 将候选人 Zach Pincus 博士转变为独立研究者的发展计划，以及 随附的研究计划描述了关于个体寿命决定因素的拟议实验， 身体健康，抗压能力强。候选人平卡斯博士是耶鲁大学博士后研究员，在平卡斯博士的实验室工作。 分子、细胞和发育生物学系的 Frank Slack。这份工作成就了他的 斯坦福大学生物医学信息学研究生学位在 Julie Theriot 博士的实验室进行 在斯坦福大学生物化学系，专注于表示和比较 单细胞群体的形状。在 Theriot 实验室，Pincus 博士随后将这些工具应用于生物物理学 研究复杂和大规模组织的分子决定因素，例如细胞形状和 移动。指导和职业发展计划将补充他的背景，这是平分的 在实验室生物学和计算方法开发之间进行培训和指导，并且 该项目涉及的具体领域：衰老生物学、线虫生物学、数学分析 动力系统和光学显微镜。平卡斯博士的目标是成为一名教员 跨学科生物科学、发育生物学或学术、私立或类似部门 政府设施，他可以在其中研究个体间变异的生物学及其与 寿命测定。这项关于个体差异的研究需要开发一种新颖的检测系统 Pincus 博士的研究成果使得人们可以通过光学显微镜检查线虫个体的整个生命周期。这 项目建议测量相关生理的各种荧光报告基因的早期水平 过程，包括胰岛素信号传导、发育稳健性和应激反应，并确定 如果这些过程中的任何一个决定了以后的寿命和健康。该项目进一步建议 通过几种独立的调查途径来确定是否存在明显的长期、压力- 抵抗力“强健”的动物群体，与更“虚弱”的个体不同，正如长期以来所提出的那样 文学。这项工作对人类健康和长寿具有明确而重大的影响。鉴定 预测或确定未来抗压性、稳健性和寿命的生物标志物，目前正在研究中 极其罕见，对老龄化社会具有重要价值，因为这些标记可能会导致 适当的延长寿命干预措施以及针对高危人群的能力。