Environmental Epigenomics and Precision Environmental Health

环境表观基因组学和精准环境健康

基本信息

批准号：
10376363
负责人：
Dana Dolinoy
金额：
$ 89.16万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-11 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376363
关键词：
Advanced Development Affect Animal Model Animals Azacitidine Belief Biological Availability Birth Blood specimen Brain Cells Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Methylation Disease Disease susceptibility Endocrine Endocrine Disruptors Environmental Health Epidemiology Epigenetic Process Exposure to Gene Expression Genes Germ Lines Goals Health Heritability Human Human Cell Line In Vitro Lead Life Malignant Neoplasms Metals Mitotic Modification Mus Mutate Outcome Perinatal Exposure Physiological RNA Research Research Support Research Training Resources Risk Rodent Sampling Somatic Cell System Technology Therapeutic Tissues Toxicant exposure Toxicology Untranslated RNA Vision base cell type cohort disorder risk epigenome epigenome editing epigenomics experimental study flexibility genomic locus human tissue imprint in vivo innovation mouse model phthalates sex tool toxicant transcription activator-like effector nucleases

项目摘要

Abstract Toxicant exposures early in life adversely affect health outcomes in both animal models and humans, in part due to epigenetic mechanisms. Accumulating studies also indicate that exposures' impact on the epigenome can be tissue and even cell specific. Yet, toxicoepigenetic animal studies are often conducted with single tissues in bulk and/or limited epigenomic targets (e.g. DNA methylation). Additionally, epigenetic epidemiology analysis of toxicants is almost always restricted to biologically available, “surrogate” (e.g. blood) samples. Using a combination of toxicological and epidemiological approaches, the first of two overarching goals of this Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) application is to advance the understanding of the effects of representative perinatal exposures (e.g. metals including lead and endocrine active compounds including phthalates) on the epigenome and longitudinal health risks. To accomplish this, we will use human physiologically relevant mouse models and longitudinal human birth cohort samples alongside targeted and unbiased approaches to evaluate DNA methylation, non-coding RNA, chromatin structure, and gene expression in both sexes in multiple tissues, incorporating single cell approaches when relevant. Ultimately, we seek to identify tissue-specific epigenomic signatures of exposures contributing to disease susceptibility as well as regions of the epigenome that may be interrogated with the use of surrogate tissues. While precision modification of the epigenome holds great promise to modify environmentally induced changes and reduce disease risk, it is currently out of reach using common available global (e.g. azacytidine) and targeted (e.g. TALENs, CRISPR) systems. Thus, our second overarching goal is to advance the development of a suite of tools, based on the PIWI-interacting RNA (piRNA) system to transform precision environmental health, while avoiding drawbacks of current technology. In mice, we have shown that piRNA and associated processing machinery are present and active in somatic tissues, especially the brain, in contrast to prior belief that the piRNA suppression system was restricted to the germ-line. Evidence from our viable yellow agouti (Avy) mouse experiments supports piRNA-based DNA methylation induction in vivo. Thus, we propose to use this class of RNA to develop precision environmental health tools to target specific genes and loci for stable, mitotically heritable, silencing in somatic cells. First, we will evaluate piRNA/PIWIL machinery across somatic human tissues to prioritize cell types with high endogenous piRNA machinery for epigenetic editing. Then, we will develop synthetic piRNAs to target DNA methylation in vitro in exposed rodent and human cell lines. The research will expand the repertoire of human epigenome editing tools resulting in therapeutics to treat a broad array of environmental and epigenetic diseases including imprinted gene disorders and cancer. The vision for the flexible and sustained RIVER support is to innovate the field of environmental epigenomics, develop translational tools for precision epigenome editing, and be a resource for research and training.

抽象的生命早期的有毒物质暴露会对动物模型和人类的健康状况产生不利影响，部分原因是由于表观遗传机制。可以是组织，甚至是细胞。整体和/或有限的表观基因组靶标（例如DNA甲基化）对有毒物质的分析几乎总是仅限于生物学上的“替代”（例如血液）样本。结合了毒理学和流行病学方法，这是两个总体目标中的第一个革命性创新，有远见的环境健康研究（河流）的应用是为了推动您理解代表性围产期暴露的代表的影响（例如金属和内分泌的金属包括邻苯二甲酸酯的活性化合物）在表观基因组和纵向健康风险上将使用人类生理学相关的小鼠模型和纵向人类出生队列样本靶向和公正的方法来评估DNA甲基化，非编码RNA，染色质结构，并且在多裂组织中，两个性别中的基因表达，相关时结合了单细胞方法。最终，我们试图确定组织特异性的表观基因组学特征，导致了导致疾病的暴露易感性以及表观基因组的区域，可以使用替代组织询问。虽然表观基因组的精确修改具有巨大的希望，可以改变环境引起的变化并降低疾病的风险，目前使用常见的全球（例如Azacytidine）和有针对性的（例如Talens，CRISPR）系统。一套工具，基于PIWI相互作用的RNA（PIRNA）系统，以转化精确的壳。健康，避免了当前技术的缺点。与优先相比 PIRNA抑制系统仅限于种植线。（Avy）小鼠实验支持基于PIRNA的DNA甲基化指示，因此我们建议使用使用。这类RNA开发精确的环境健康工具工具wort虫特定基因和基因座，以稳定，有丝分裂的遗传，在体细胞中沉默。人体组织以表观遗传编辑的内源性piRNA机制优先考虑细胞类型将在暴露的啮齿动物和人类细胞系中发展合成的PIRNA，以靶向DNA甲基化研究将扩大人类表观基因组编辑工具的曲目，从而使治疗剂相信广泛一系列环境和表观遗传疾病，包括印迹基因疾病和癌症。灵活而持续的河流支持是创新表观基因组学领域，发展精确表观基因组编辑的翻译工具，并成为研究和培训的资源。