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，使用在新型系统中饲养的遗传上相同的秀丽隐杆线虫，使个人得以 一生都在孤立的，相同的环境中被追随。使用此方法的初步研究 确定了胰岛素/IGF-1样信号的microRNA调节剂，该信号在成人的早期可以预测几乎一半 以后的寿命变异性。这种“通往独立途径”奖项申请包括指导职业 候选人扎克·潘塞斯（Zach Pincus）博士向独立研究者的发展计划 随附的研究计划描述了有关单个寿命的决定因素的拟议实验， 健康和抗压力。候选人Pincus博士是耶鲁大学的博士后研究员。 分子，细胞和发育生物学系的弗兰克·斯洛克（Frank Slack）。导致他的工作 斯坦福大学生物医学信息学研究生学位是在朱莉·塞里奥特（Julie Theriot）博士的实验室中进行的 在斯坦福生物化学部，专注于代表和比较的算法 单细胞种群的形状。在Theriot实验室中，Pincus博士随后将这些工具应用于生物物理 关于复杂和大刻度组织的分子决定因素的研究，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，该背景均匀分裂 在基准生物学和计算方法开发之间，每种培训和指导以及 该项目涉及的特定领域：老化生物学，线虫生物学，数学分析 动力学系统和光学显微镜。 Pincus博士的目标是成为 学术，私人或 政府设施，他可以在其中研究个体间可变性的生物学及其与之相关的生物 寿命确定。这项关于个人间变异性的研究需要开发出新的测定系统 Pincus博士允许单个秀丽隐杆线虫在一生中通过光学显微镜检查。这 项目建议测量相关生理学的各种荧光记者的早期水平 包括胰岛素信号传导，发育鲁棒性和压力反应在内的过程，并确定 如果这些过程中的任何一个都决定了以后的寿命和健康。该项目进一步提议 通过几个独立的研究途径确定是否存在明显的长寿，应力 - 耐药的动物队列，与更多“脆弱”个体不同，就像长期以来提出的那样 文学。这项工作对人类健康和寿命具有明显的重要意义。识别 预测或确定未来压力，鲁棒性和寿命的生物标志物，目前是 极为罕见的人对衰老的社会具有很大的价值，因为这样的标记可能会导致发展 适当的寿命繁殖干预措施以及将其定位为处于危险人群的能力。