Integrating environment-by-epigenome interactions into a tractable model of epigenetic aging

将环境与表观基因组的相互作用整合到易于处理的表观遗传衰老模型中

基本信息

批准号：
10674255
负责人：
Benjamin Barrow Parrott
金额：
$ 27.34万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-02 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674255
关键词：
Acute Address Affect Age Aging Air Automobile Driving Biological Biological Aging Biological Markers Biological Process Chronic Chronology Climate Clinical Research Communities Complex DNA Development Disasters Disease Dose Dose-Rate Elderly Environment Environmental Exposure Environmental Pollution Environmental Risk Factor Epigenetic Process Event Exposure to Facility Designs Fishes Genetic Genome Genomics Goals Health Heart Diseases Individual Ionizing radiation Japanese Killifish Life Life Cycle Stages Link Longevity Malignant Neoplasms Measures Mediating Medical Methylation Modeling Molecular Nature Nuclear Accidents Nuclear Energy Nuclear Warfare Nucleotides Occupational Exposure Oryziinae Outcome Pattern Performance Physiological Physiology Play Process Public Health Radiation Radiation Accidents Radiation exposure Recording of previous events Regimen Reproductive Health Resolution Resources Risk Rivers Role Shapes Site Social Environment Terrorism Testing Time Toxicology Travel Work age related aquatic organism base combinatorial density design dirty bomb disorder risk epigenome experience irradiation life history methylome middle age mortality novel programs radiation risk response social stem stressor theories

项目摘要

Project Summary The goal of the project is to discover how the environment interacts with epigenetic aging processes to affect biological aging. Risk of radiation exposure occurring through occupational exposures, medical therapies, or environmental disasters involving ionizing radiation (IR), either due to nuclear accidents, nuclear warfare, and/or terrorist attacks (e.g., attacks on nuclear energy facilities, dirty bombs) are acutely relevant to contemporary public health. However, health impacts resulting from such exposures are difficult to predict due to variable dose rates, duration of exposure, age-specific effects, and the environmental and social context of exposure. Although testing the outcome of each combinatorial scenario isn’t feasible, a fundamental understanding of how environmental and age-dependent variables interact with IR exposure can be achieved through approaches that incorporate environmental complexity and realistic dosing regimens. Recent advances demonstrate a role for the epigenome in biological aging as it provides a molecular context for integrating both genetic and environmental influences into aging programs. Epigenetic clocks summarize the readout of age associated hyper- and hypo-methylation from a selection of loci across the genome which are collectively capable of predicting chronological age with high accuracy. Despite their unprecedented accuracy, the age indicated by epigenetic clocks can differ from an individual’s actual age. The magnitude and directionality of this epigenetic-to-chronological age mismatch is associated with physiological function and disease risk. For example, advanced epigenetic age relative to their chronological age is associated with cancer, heart disease, and all-cause mortality. The underlying causes of epigenetic-to-chronological age discordance are not resolved but both genetic and environmental factors appear to play a role. To empirically address causal relationships between environmental conditions and epigenetic aging, this project will take advantage of recently developed epigenetic clocks for the experimentally and genetically tractable medaka fish (Oryzias latipes) model. The work encompasses three primary objectives: (1) Test the hypothesis that chronic exposure to environmentally relevant doses of ionizing radiation accelerate and shape epigenetic aging trajectories. (2) Determine how an individual’s developmental exposure history interacts with subsequent radiation exposure to affect biological aging trajectories. (3) Identify windows of vulnerability occurring across the lifespan in which environmental exposures disproportionately impacts epigenetic aging trajectories. Together, this work will advance a life course and toxicological understanding of how environmental challenges associated with radiological disaster events shape biological aging and attendant organismal physiology.

项目摘要该项目的目的是发现环境如何与表观遗传衰老过程相互作用以影响生物衰老。通过职业暴露，医疗疗法或涉及电离辐射（IR）的环境灾难，要么是由于核战争，核战争，和/或恐怖袭击（例如，对核能设施的攻击，肮脏的炸弹）与当代公共卫生。但是，由于这种暴露造成的健康影响很难预测可变剂量率，暴露持续时间，特定年龄效果以及环境和社会背景曝光。尽管测试每种组合场景的结果是不可行的，但是基本的了解如何实现环境和年龄依赖性变量与IR暴露的相互作用通过结合环境复杂性和现实给药方案的方法。最近的进步证明了表观基因组在生物衰老中的作用，因为它提供了分子环境将遗传和环境影响整合到衰老计划中。表观遗传时钟摘要从基因组中选择基因群选择的年龄相关的超级和低甲基化的读数，该基因组的选择共同能够以高精度来预测年龄。尽管他们前所未有精度，表观遗传时钟指示的年龄可能与个人的实际年龄有所不同。大小和这种表观遗传到女性年龄不匹配的方向性与身体机能和疾病风险。例如，高级表观遗传年龄相对于其年代年龄与癌症，心脏病和全因死亡率。表观遗传到人类学年龄的根本原因不一致无法解决，但遗传因素和环境因素似乎都起作用。经验解决环境状况与表观遗传衰老之间的因果关系，该项目将进行最近开发的表观遗传钟的优势用于实验和遗传性的Medaka鱼（oryzias latipes）模型。这项工作包括三个主要目标：（1）检验以下假设：长期暴露于与环境相关的电离辐射剂量加速并形成表观遗传衰老轨迹。（2）确定个人的发育暴露历史如何与随后的辐射暴露相互作用影响生物衰老轨迹。（3）确定在整个生命周期中发生的脆弱性窗户环境暴露不成比例地影响表观遗传衰老轨迹。在一起，这项工作将提高人生课程和对环境挑战如何相关的毒理学理解放射灾难事件塑造生物衰老和随之有机生理学。