GENETICS, GENOMICS, AND MOLECULAR CORE

6.5.建议的遗传学、基因组学和分子资源核心(RC-2)活动概述： 6.5.a)具体目标：RC-2的目的是提供人力资源、基础设施和培训 为了促进与脆弱性有关的最高质量的当代生物学研究，总的重点是 霍普金斯OAIC。这个核心为脆弱的研究人员提供的资源将包括1)领先的跨学科 设计和实施与以下方面有关的分子、遗传和基因组研究的专门知识 脆弱性；2)获得最先进的遗传、基因组和分子技术；3)获得各种 人类和虚弱动物模型DNA、组织和血清样本；4)遗传学方面的指导和培训， 基因组学和分子生物学；以及5)帮助将分子、遗传和基因组研究成果转化为 具有临床意义的干预措施。通过提供这些智力和物质资源，RC-2将促进 阐明构成脆弱和相关生物脆弱性的临床相关生物途径， 从而确定有希望的目标，以针对这些目标制定预防或减轻脆弱性的干预措施。 RC-2项目最初几年的资金通过以下方式在实现这些目标方面取得了重大进展： 建立与脆弱性有关的基因数据生成和分析的最先进基础设施； 聚集了一支由经验丰富的高技能多学科研究人员组成的团队；以及重要的科学研究 与脆弱性有关的进展，包括开发新的内表型，确定关键的 与虚弱有关的分子途径，以及虚弱小鼠模型的发展。结果就是这样 进步，RC-2及其领导层已成为开发与衰老相关的脆弱和衰老的国家资源 遗传学研究通过出版物、获奖的国家研讨会、联盟建设来衡量 努力将老年人群体结合起来，开发和资助合作遗传学研究 与全国各地的调查人员合作，并为下一代投资者提供培训和指导 对研究脆弱的分子和遗传基础并将其转化为临床护理感兴趣。 尽管RC-2赞助的调查人员已经取得了实质性的科学进步，并解决了许多 最初的资源挑战，脆弱性基本调查的下一个阶段需要解决新发现的问题 在检验从第一个供资周期产生的数据中产生的新假说方面面临挑战。至 应对这些挑战，并测试与脆弱性相关的下一代假设，我们建议 将RC-2的范围从人类遗传学研究扩展到综合遗传学、基因组学和 分子核心，建立在最初几年发展起来的科学、基础设施和专业知识的基础上 这个中心。这一演变将需要利用其他人力和基础设施资源 在约翰·霍普金斯大学的医疗机构中，促进脆弱的研究，包括促进老年人的接触 具有必要的专业知识和基础设施以a)促进分析所需的分析战略的领导者 正在产生大量的遗传学和基因组学数据，b)包括氧化测量 压力，线粒体！功能、DNA甲基化和基因表达进入RC-2资助的脆弱性研究， 和c)改进获取人类和/或动物生物样本和表型数据的途径，以满足需要 用于其他脆弱的研究。这一下一阶段的目标和进展将使RC-2能够继续支持 与脆弱有关的最严格的人类基因研究，同时使其能够扩大其范围 以支持在与人类脆弱相关的遗传学研究中确定的分子途径的研究。

6.5. Overview of Proposed Genetics, Genomics and Molecular Resource Core (RC-2) Activities: 6.5.a) Specific Aims: The purpose of RC-2 is to provide the human resources, infrastructure, and training necessary to facilitate the highest quality contemporary biological studies related to frailty, the overall focus of the Hopkins OAIC. The resources provided by this core to frailty researchers will include 1) leading interdisciplinary expertise for the design and implementation of molecular, genetic and genomic studies related to frailty; 2) access to state-of-the-art genetic, genomic and molecular technologies; 3) access to a diversity of human and frail animal model DNA, tissue and serum samples; 4) mentorship and training in genetics, genomics, and molecular biology; and 5) expertise to help translate molecular, genetic and genomic findings to clinically meaningful interventions. By providing these intellectual and physical resources, RC-2 will facilitate the elucidation of clinically relevant biological pathways that underlie frailty and related biological vulnerability, and thereby identify promising targets toward which to develop interventions that prevent or attenuate frailty. The first years of RC-2 funding have produced significant progress towards these goals through: the establishment of state-of-the-art infrastructure for genetic data generation and analyses related to frailty; the assemblage of a highly-skilled multidisciplinarv team of experienced investigators; and important scientific progress related to frailty, including the development of novel endophenotypes, the identification of critical molecular pathways associated with frailty, and the development of a frail mouse model. As a result of this progress, RC-2 and its leadership has become a national resource for the development of frailty and agingrelated genetics research as measured by publications, award-winning national symposia, consortium building efforts for combining populations of older adults, development and funding of collaborative genetics studies with investigators across the country, and provision of training and mentorship for the next generation of investgators interested in studying the molecular and genetic basis of frailty and its translation into clinical care. Although RC-2 sponsored investigators have made substantial scientific progress and have resolved many initial resource challenges, the next stages of basic investigation of frailty require resolution of newly identified challenges in order to test novel hypotheses originating from data generated in the first cycle of funding. To address these challenges, and to test the next generation of hypotheses related to frailty, we propose to expand the scope of RC-2 beyond human genetics studies into a comprehensive genetics, genomics, and molecular core that builds on the evolving science, infrastructure, and expertise developed in the first years of this center. This evolution will require the leveraging of additional human and infrastructure resources from across the Johns Hopkins Medical Institutions towards frailty research, and include facilitating access to senior leaders with necessary expertise and infrastructure to a) facilitate analytical strategies needed to analyze the vast amounts of genetics and genomics data being generated, b) incorporate measurements of oxidative stress, mitochondria! function, DNA methylation, and gene expression into RC-2 sponsored frailty research, and c) develop improved access to human and/or animal biological samples and phenotypic data for needed for additional frailty research. This next stage of goals and advances will enable RC-2 to continue to support the most rigorous human genetic studies related to frailty while at the same time enable it to expand its scope to support studies of molecular pathways identified in genetics studies related to human frailty.