Epigenetic Drivers of Intrinsic Phenotypic Variability in Metabolic Disease

代谢疾病内在表型变异的表观遗传驱动因素

• 批准号: 9978061
• 负责人: ANDREW P. FEINBERG
• 金额: $ 78.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978061
• 关键词: Address; Affect; Area; Controlled Environment; Data; Development; Developmental Biology; Diabetes Mellitus; Diagnostic; Environment; Epigenetic Process; Evolution; Exposure to; Future; Genetic; Genome; Human; Hybrids; Inbreeding; Incidence; Individual; Intervention; Knowledge; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Noise; Nutritional; Obesity; Persons; Phenotype; Predisposition; Reproducibility; Research; Sex Differences; Signal Transduction; Testing; Therapeutic; Translating; United States National Institutes of Health; Work; catalyst; epigenome; epigenomics; genetic testing; improved; innovation; metabolic phenotype; precision medicine; prenatal; response; theories

The purpose of this Catalyst project is to apply a highly innovative general theory that integrates evolution, developmental biology, and epigenetics, to metabolic disease and diabetes. The underling premise is that intrinsic variability in phenotype from individual to individual, even with an identical genome, is not simply noise, but is itself in part a signal with adaptive value in evolution, development, and response to the environment. Moreover, this variability is mediated through the epigenome, has profound effects on metabolism, and is in turn affected by metabolic signals in the environment during development. If this hypothesis is even in part correct, the proposed work would provide at least partial solutions to arguably two of the most important problems facing NIDDK, and NIH as a whole: (1) How can we apply genetic testing, or precision medicine more generally, if the intrinsic variability from person to person is great, even with ideally complete genetic knowledge? and (2) Is data irreproducibility in fact driven partly by inherent and adaptive variability that carries information of critical diagnostic and therapeutic importance? This provocative idea has transformative implications for how we approach the application of precision medicine to address the growing incidence of obesity and metabolic syndrome. Existing data using reproducible genomes, such as inbred or F1 hybrid mice, in highly controlled environments, clearly shows the existing of inherent variability in metabolic phenotypes. To elucidate the underlying origins of this variability and to develop a paradigm to exploit this knowledge to improve the accuracy of precision medicine as applied to metabolic disease, we will (1) measure the degree of phenotypic plasticity in genetically identical mice, testing within-litter inter-mouse variability, inter-litter variability, and inter-strain variability; (2) determine the effect of prenatal nutritional perturbation on phenotypic and epigenetic plasticity; (3) translate these findings to assessing the accuracy of human metabolic disease precision medicine; and (4) investigate sex differences in epigenomic and phenotypic variability. This highly innovative proposal represents a completely new direction for my research, and could have profound influence on our understanding of the developmental origins and associated variability in susceptibility to metabolic disease, with profound implications on future interventions using precision medicine paradigms.

该催化剂项目的目的是应用一种高度创新的一般理论，该理论整合进化， 发育生物学和表观遗传学，用于代谢疾病和糖尿病。下一个前提是 从单个到个体的表型的内在变异性，即使具有相同基因组，也不只是噪声，而是 但本身就是一个信号，具有自适应价值，对环境的进化，发展和响应。 此外，这种可变性是通过表观基因组介导的，对新陈代谢有深远的影响，而又是 在开发过程中受环境中的代谢信号的影响。如果此假设甚至部分正确， 拟议的工作将至少提供部分解决方案，可以说是两个最重要的问题 NIDDK和NIH的整体：（1）如果我们如何应用基因检测或精确医学，如果 人与人之间的内在变异性也很大，即使具有理想的完全遗传知识？ （2）是数据 实际上，不可重复的性能部分是由固有和适应性变异性驱动的，这些可变性带有关键信息 诊断和治疗重要性？这个挑衅的思想对我们的方式具有变革性的影响 处理精确药物的应用来解决肥胖和代谢的日益增长的发生率 综合征。使用可重现的基因组（例如近交或F1混合小鼠）的现有数据，高度控制 环境清楚地显示了代谢表型中固有可变性的现有。阐明 这种变异性的根本起源并开发范式以利用这种知识以提高准确性 用于代谢疾病的精确医学，我们将（1）测量表型可塑性的程度 基因相同的小鼠，测试液体内鼠间变异性，插槽间变异性和紧通间 可变性； （2）确定产前营养扰动对表型和表观遗传可塑性的影响； （3） 将这些发现转化为评估人类代谢疾病精度药物的准确性； （4） 研究表观基因组和表型变异性的性别差异。这个高度创新的建议代表 对于我的研究，一个全新的方向，可能会对我们对 发育起源和对代谢疾病易感性的变异性，具有深远的影响 关于未来的干预措施，使用精密医学范例。