Functional Genomics

摘要 这项名为“呼吸道疾病的系统生物学”的综合计划项目资助的目标是确定 哮喘和COPD之间有共同的遗传、基因组和表观遗传学特征，这是最常见的两种疾病 慢性肺部疾病。目标是将人类遗传学和基因组学转化为生物学，并最终受益 疾病治疗，这种PPG不同于其他系统生物学方案，因为它全面 功能评估流水线，其中包括对遗传变异的一系列功能验证，候选 哮喘和COPD之间共享的基因和网络模块。这样的功能验证将大大加快 建立并优先考虑候选疾病基因作为治疗靶点。核心C将提供全面的功能支持 这个PPG中的所有项目。核心C的功能包括：(1)鉴定功能GWAs和测序 与哮喘和COPD的气流阻塞相关的变种(项目1)；(2)实验研究 验证建立在哮喘和COPD受试者遗传学、基因组学和表观遗传学基础上的疾病模块 (项目1、2和3)；(3)建立与哮喘和哮喘相关的细胞表型筛选模型 COPD和应用RNAi功能丧失方法在该模型中评估新的疾病基因(项目2 3)；(4)模拟吸烟对原代人支气管上皮DNA甲基组的影响 单元格(项目3)。我们将为所有项目提供必要的生物咨询和支持。为了实现这些目标 核心C的功能，因此，确保成功完成这一PPG，核心C由三个组装 资深细胞生物学家周晓波博士指导的高级研究助理 功能基因组实验室，将由资深分子生物学家马克·佩雷拉博士协助 布里格姆妇女医院肺部和重症监护医学部的肺科医生，以及 周博士和PPG的其他几名关键调查人员的长期合作伙伴。C核心是基于一口井- 配备了分子和细胞生物学实验室，可以获得所有需要的资源。另外，周博士 是所有项目首席调查员Scott Weiss博士、Benjamin Raby博士和 道恩·德梅奥。他们拥有证明的成功记录和工作效率，这将确保Core C 满足该PPG的整体功能需求。

ABSTRACT The goal of this integrative program project grant, “Systems Biology of Airway Disease”, is to identify the shared genetic, genomic and epigenetic features between asthma and COPD, two of the most common chronic lung diseases. Aiming to translate human genetics and genomics to biology and eventually benefit disease treatment, this PPG differs from other systems biology proposals because of its comprehensive functional assessment pipelines, which include a series of functional validations on genetic variants, candidate genes and network modules shared between asthma and COPD. Such functional validation will greatly speed up and prioritize candidate disease genes as therapeutic targets. Core C will provide overall functional support to all projects in this PPG. The function of Core C includes: (1) identifying functional GWAS and sequencing variants that are associated with airflow obstruction in both asthma and COPD (Project 1); (2) experimentally validating disease modules built upon genetics, genomics and epigenetics from asthma and COPD subjects (Projects 1,2 and 3); (3) establishing a cellular phenotypic screening model that is relevant to asthma and COPD and applying loss-of-function approach by RNAi in this model to assess novel disease genes (Project 2 and 3); (4) modeling cigarette smoke induced DNA methylome changes in primary human bronchial epithelial cells (Project 3). We will provide needed biological consulting and support to all projects. To fulfill these functions of Core C and, thus, ensure successful completion of this PPG, Core C is assembled with three senior research assistants directed by the experienced cell biologist, Dr. Anny Xiaobo Zhou, the Director of Functional Genomics Laboratory who will be assisted by Dr. Mark Perrella, a senior molecular biologist and pulmonologist in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, and a longtime collaborator of Dr. Zhou and several other key investigators of the PPG. Core C is based on a well- equipped molecular and cell biology laboratory that has access to all needed resources. In addition, Dr. Zhou has been a longtime collaborator of all Project Principal Investigators, Drs. Scott Weiss, Benjamin Raby and Dawn DeMeo. They have a demonstrated successful track record and productivity that will ensure Core C will meet the overall functional needs of this PPG.