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The Duke FUNCTION Center: Pioneering the comprehensive identification of combinatorial noncoding causes of disease

杜克大学功能中心：开创了疾病组合非编码原因的全面识别

基本信息

批准号：
10271500
负责人：
ANDREW S ALLEN
金额：
$ 248.99万
依托单位：
DUKE UNIVERSITY
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：
2020-09-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10271500
关键词：
Duke FUNCTION Center Pioneering comprehensive

项目摘要

ABSTRACT: Noncoding genetic variation that alters gene regulatory element activity has major impacts on health, disease, and evolution. Because measuring regulatory element activity has long been a major challenge, the mechanisms underlying thousands of genetic associations with disease remain unknown. Recent advances in high-throughput technologies have disruptively advanced the ability to measure the activity of individual regulatory elements, and the first population- and genome-scale uses of those methods are now underway. However, regulatory elements do not act alone. They interact with promoters, other regulatory elements, and the surrounding chromatin, all in ways that are complex and difficult to predict. Though there are now a plethora of technologies to measure the activity of individual regulatory elements, the ability to recapitulate the effects of combinations of regulatory elements is woefully inadequate and severely hinders efforts to establish the gene regulatory contributions to traits and diseases. The goal of the Duke FUNCTION Center of Excellence in Genomic Science is to make the study of the combinatorial activity of regulatory elements routine. Aim 1 is to develop a suite of new technologies to measure the combinatorial effects of regulatory elements in their endogenous genomic contexts. Those technologies will leverage very recent discoveries of CRISPR enzymes other than Cas9 that greatly expand the ability to manipulate the human genome. Aim 2 is to develop the matched computational, statistical, and evolutionary models needed to interpret and predict the measured effects of combinations of regulatory variants on human traits and diseases. Aim 3 is to demonstrate the broad applicability of the technologies developed through case studies of human diseases with prevalence ranging from common to ultra rare. Example case studies will include studies of schizophrenia, rare recessive disorders, and undiagnosed genetic disorders. We will also use a nationwide request for applications to identify Pilot Projects that will expand applications to other disease areas. Aim 4 is to create an electronic platform for distributing results from functional studies of the noncoding genome to the broad research community. The platform will integrate our results with those from studies in other labs and consortia, such as ENCODE; and will enable researchers with diverse expertise to benefit from the Center. Finally, our Education and Outreach Aim is to expand genomics capacity locally and nationally, and with a particular emphasis on increasing use of our new technologies for translational research. The expected outcome of this project will be a paradigm shift in human genetic and genomics in which it will become possible to finally understand the full regulatory complexity that controls the expression of human genes. We anticipate that ability will be particularly powerful for translating genetic associations into disease mechanisms, thus creating a windfall of new knowledge about which genes contribute most to disease, and how to manipulate those genes for therapeutic benefit. Long term, we envision this work being critical to realizing the full potential of whole genome sequencing to detect causes of disease.

摘要：改变基因调控元件活性的非编码遗传变异对健康、疾病和进化。因为衡量监管要素的活动长期以来一直是一项重大挑战，数以千计的基因与疾病相关的潜在机制仍不清楚。最新进展高通量技术颠覆性地提高了衡量个人活动的能力监管要素，以及这些方法的第一次群体和基因组规模的使用现在正在进行。然而，监管因素并不是单独行动的。它们与发起人、其他监管元素以及围绕着染色质，所有的方式都是复杂的，很难预测。尽管现在有太多的衡量单个监管要素的活动的技术，概括影响的能力调控元素的组合严重不足，严重阻碍了建立该基因的努力对性状和疾病的监管贡献。杜克大学卓越功能中心的目标是基因组科学是使对调控元件组合活性的研究常规化。目标 1是开发一套新技术来衡量其监管元素的组合效应内源基因组环境。这些技术将利用CRISPR酶的最新发现而不是Cas9，这大大扩展了操纵人类基因组的能力。目标2是开发匹配的解释和预测测量的影响所需的计算、统计和进化模型人类特征和疾病的调控变异的组合。目标3是展示其广泛的适用性。通过人类疾病个案研究开发的技术，其流行率从常见的变得极其稀有。范例案例研究将包括对精神分裂症、罕见隐性障碍和未确诊的遗传性疾病。我们还将利用全国性的申请申请来确定试点项目这将扩大到其他疾病领域的应用。目标4是创建一个电子分发平台从非编码基因组的功能研究到广泛的研究社区的结果。该平台将将我们的结果与ENCODE等其他实验室和联盟的研究结果相结合，并将使拥有不同专业知识的研究人员将从该中心受益。最后，我们的教育和外展目标是扩大当地和全国的基因组学能力，并特别强调增加我们新的翻译研究的技术。这个项目的预期结果将是人类的范式转变遗传学和基因组学，它将有可能最终理解控制人类基因的表达。我们预计，这种能力在翻译方面将特别强大基因与疾病机制的关联，从而创造了关于哪些基因的意外之财对疾病的贡献最大，以及如何操纵这些基因以获得治疗效益。从长远来看，我们设想这项工作对于实现全基因组测序检测疾病原因的全部潜力至关重要。