Epigenetic Drivers of Intrinsic Phenotypic Variability in Metabolic Disease

这个催化剂项目的目的是应用一个高度创新的综合进化论的一般理论， 从发育生物学、表观遗传学到代谢性疾病和糖尿病。基本的前提是 个体之间表型的内在差异，即使是完全相同的基因组，也不仅仅是噪声， 但它本身在一定程度上是一种信号，在进化、发展和对环境的反应中具有适应价值。 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，并反过来 在发育过程中受环境中代谢信号的影响。如果这一假设部分是正确的， 拟议的工作将至少为可以说是两个最重要的问题提供部分解决方案 NIDDK和NIH作为一个整体：(1)我们如何应用基因检测，或更普遍的精确医学，如果 人与人之间的内在差异是巨大的，即使拥有理想的完整的基因知识？和(2)是数据 不可再生性事实上部分是由携带关键信息的固有的和适应性的可变性驱动的 诊断和治疗的重要性？这一挑衅性的想法对我们如何 探讨应用精确医学解决肥胖和新陈代谢发病率上升的问题 综合症。使用可复制基因组的现有数据，如近交系或F1杂交小鼠，在高度受控 环境，清楚地表明代谢表型存在固有的变异性。为了澄清 这种可变性的潜在起源，并开发一种范例来利用这一知识来提高准确性 关于精确医学应用于代谢性疾病，我们将(1)测量表型可塑性的程度 遗传相同的小鼠，测试窝内小鼠间变异性、窝间变异性和品系间变异性 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性疾病精准医学的准确性；以及(4) 研究表观基因组和表型变异的性别差异。这一极具创新性的提案代表了 为我的研究开辟了一个全新的方向，并可能对我们对 代谢性疾病易感性的发育起源和相关变异，具有深远的意义 关于未来使用精确医学范例的干预措施。

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.