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一般理论，整合进化， 发育生物学，表观遗传学，代谢疾病和糖尿病。基本前提是， 个体与个体之间表型的内在变异性，即使具有相同的基因组，也不仅仅是噪音， 但其本身在进化、发育和对环境的反应中部分地是具有适应价值的信号。 此外，这种变异性是通过表观基因组介导的，对代谢有深远的影响，并反过来影响代谢。 在发育过程中受到环境中代谢信号的影响。如果这个假设有一部分是正确的， 拟议中的工作将至少部分解决可以说是面临的两个最重要的问题 NIDDK和NIH作为一个整体：（1）我们如何应用基因检测，或更普遍的精准医学，如果 人与人之间的内在差异是巨大的，即使有理想的完整的遗传知识？（2）数据 事实上，不可再现性部分是由固有的和适应性的变异性驱动的， 诊断和治疗的重要性？这一挑衅性的想法对我们如何 探讨精准医学的应用，以解决肥胖和代谢性疾病发病率不断上升的问题。 综合征现有的数据使用可重复的基因组，如近交系或F1杂交小鼠，在高度控制的 环境，清楚地表明存在固有的变异性代谢表型。阐明本 这种变异性的根本起源，并开发一种范式，利用这一知识，以提高准确性 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 （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准医学的准确性;以及（4） 研究表观基因组和表型变异性性别差异。这一极具创新性的提案代表了 这是我研究的一个全新方向，可能会对我们理解 发展起源和相关的变异性，对代谢疾病的易感性，具有深远的影响 关于未来使用精准医学模式的干预措施。

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.