BIOINFOMATICS CENTER FOR INNATE IMMUNITY PGA

建议课程(改编自申请者摘要) 哮喘、慢性阻塞性肺疾病(COPD)、心肌梗塞 和深静脉血栓形成(DVT)是最常见的疾病之一 肺、心、血(参考)。这些项目的综合医疗成本 条件大约是每年1000亿美元。RFA HL的目标是- 99-024基因组在心脏、肺和血液研究中的应用正在开发中 并在心脏、肺和血液群体中扩大基因组知识 将这些知识应用于疾病病理生物学。已经有相当多的 对这些疾病发病机制的了解取得进展， 所有这四种都与局部炎症性疾病的发展有关 进程。很明显，细胞和细胞因子是细胞的一部分 先天免疫系统控制着这一过程的早期阶段， 和血管炎症。 该提案建立在三个机构的优势之上：呼吸系统 亚利桑那大学(UA)科学中心医学系 在布里格姆妇女医院(BWH)和生物信息学项目 波士顿儿童医院开发一项人类变异发现 关于非同源豁免主题的方案及其与 心脏、肺和血液疾病。亚利桑那州/BWH PGA将提供 拥有完整的遗传变异筛查的科学社区 先天免疫基因的子集，这些基因最有可能影响患病风险 上述四种疾病。调查人员还将执行一项 初步评估这些变异与四种基因的关联性 正在研究的表型，以指导这些领域的研究人员远离变异 与之相关的可能性很低，对那些表现出希望的人 影响四种疾病中任何一种的功能和流行病学证据 表型。为了实现这一广泛的目标，调查人员拥有 具体目标如下：(1)筛选100个已知基因的多态 与先天免疫反应直接或间接相关；(2)与基因 西班牙裔、非西班牙裔白人和非裔美国人的样本 对所有新发现的多态性进行种族分析；(3)执行 关联研究和系统发育分析以确定最有可能的SNPs 参与哮喘、慢性阻塞性肺疾病的检测 疾病、心肌梗塞和深静脉血栓形成；(4)传播 关于特定种族和特定表型的分布的信息 网站上正在研究的多态现象在完成后60天内 基因分型研究；(5)制定培训计划，使 具有不同知识和经验的人需要熟悉 现代基因技术在高通量测序和 基因分型.遗传学的研究设计、数据处理和数据分析 流行病学；以及人口遗传学中的伦理问题。

PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, non-Hispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics.