Tuberculosis Infection and Genetic Variation

结核感染和基因变异

• 批准号: 8460546
• 负责人: David J. Horne
• 金额: $ 12.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460546
• 关键词: Advisory Committees; Alveolar Macrophages; Area; Biological Assay; Biometry; Candidate Disease Gene; Cells; Clinical; Clinical Research; Communicable Diseases; Complex; DNA; Disease; Disease Association; Environment; Evaluation; Exposure to; Family; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Host Defense; Human; Human Resources; Immune response; Immune system; Immunologic Receptors; Immunologics; Immunology; Individual; Infection; Instruction; Interferon Type II; Investigation; Laboratories; Lung; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Modeling; Mycobacterium Infections; Mycobacterium tuberculosis; Natural Immunity; Nested Case-Control Study; Outcome; Pathway interactions; Patients; Phylogenetic Analysis; Population; Predisposition; Process; Research; Research Infrastructure; Research Personnel; Risk Factors; Role; Single Nucleotide Polymorphism; Target Populations; Toll-Like Receptor 1; Toll-like receptors; Training; Tuberculosis; Tuberculosis Vaccines; Uganda; Universities; Variant; Washington; Work; base; career; career development; case control; cohort; design; experience; gene environment interaction; genetic association; genetic epidemiology; genetic risk factor; indexing; macrophage; meetings; member; novel; pathogen; pathogen exposure; patient oriented; prophylactic; prospective; receptor; skills; transmission process; vaccine development

DESCRIPTION (provided by applicant): This K23 award will provide an opportunity for Dr. Horne to develop as an independent investigator in patient-oriented clinical research on genetic variation in innate immunity and susceptibility to tuberculosis (TB) infection. This career development application describes a comprehensive plan to accomplish the following goals: 1) assemble a cohort of patients in order to identify genetic, exposure-, and pathogen-related risk factors for TB infection, 2) develop expertise in host genetic variation and TB infection, 3) develop an understanding of the host innate immune response following an exposure to Mycobacterium tuberculosis (MTb), and 4) develop an independent clinical research career. These goals will be accomplished through mentorship by key personnel, didactic course work, instruction in practical laboratory skills, and participation in scientific meetings. We will assemble a cohort of patients in Seattle, Washington, who have a known TB exposure with the following specific aims: 1) thoroughly characterize clinical and exposure-related factors, identify MTb phylogenetic lineage from the index case, and use these factors to develop a risk factor model for TB infection; and 2) perform a nested case- control study in unrelated subjects to determine whether single nucleotide polymorphisms (SNPs) in candidate genes related to innate immunity are associated with TB infection. In our analysis of genetic associations, we will adjust for significant clinical, exposure and pathogen-related risk factors identified in Aim 1. We will confirm genetic associations in a previously collected family- based cohort. This study is novel for the outcome of TB infection and the inclusion of MTb lineage. The rich academic environment at the University of Washington is ideal for Dr. Horne's training and has allowed him to assemble an advisory committee whose members possess expertise in innate immunology, MTb phylogenetics, genetic epidemiology, biostatistics, risk factor modeling and TB transmission. Dr. Hawn, the primary mentor, is a successful and recognized expert in innate immunity, especially pathogen recognition receptors and associated pathways. He has investigated the role of Toll-like receptors (TLRs) in mycobacterial infection in functional and genetic association studies. Dr. Peter Small, co-mentor, is an internationally recognized expert in MTb phylogenetics. /Relevance TB infection, compared to TB disease, is an understudied area and little is known about host genetics and susceptibility to TB infection. TB is estimated to infect one-third of the global population and findings from this study could be important to TB vaccine development. Findings may also have relevance to other infectious diseases.

描述（由申请人提供）：该 K23 奖项将为 Horne 博士提供一个机会，使其成为一名独立研究者，从事以患者为导向的先天免疫遗传变异和结核病 (TB) 感染易感性临床研究。该职业发展申请描述了实现以下目标的综合计划：1) 组建一组患者，以确定结核感染的遗传、暴露和病原体相关风险因素，2) 培养宿主遗传变异和结核感染方面的专业知识，3) 了解暴露于结核分枝杆菌 (MTb) 后宿主先天免疫反应，4) 发展独立的临床研究职业。这些目标将通过关键人员的指导、教学课程、实用实验室技能指导以及参加科学会议来实现。我们将在华盛顿州西雅图召集一组已知有结核病暴露的患者，其具体目标如下：1）彻底描述临床和暴露相关因素，从指示病例中识别 MTb 系统发育谱系，并利用这些因素开发结核病感染的危险因素模型； 2）在不相关的受试者中进行巢式病例对照研究，以确定与先天免疫相关的候选基因中的单核苷酸多态性（SNP）是否与结核病感染相关。在我们对遗传关联的分析中，我们将针对目标 1 中确定的重要临床、暴露和病原体相关风险因素进行调整。我们将在之前收集的基于家庭的队列中确认遗传关联。这项研究对于 TB 感染的结果和 MTb 谱系的纳入是新颖的。华盛顿大学丰富的学术环境非常适合霍恩博士的培训，并使他能够组建一个咨询委员会，其成员拥有先天免疫学、MTb 系统发育学、遗传流行病学、生物统计学、危险因素建模和结核病传播方面的专业知识。主要导师 Hawn 博士是先天免疫领域的一位成功且公认的专家，特别是病原体识别受体和相关途径。他通过功能和遗传关联研究研究了 Toll 样受体 (TLR) 在分枝杆菌感染中的作用。联合导师 Peter Small 博士是国际公认的 MTb 系统发育学专家。 /相关性 与结核病相比，结核感染是一个研究不足的领域，人们对宿主遗传学和结核感染的易感性知之甚少。据估计，结核病感染了全球三分之一的人口，这项研究的结果对于结核病疫苗的开发可能很重要。研究结果也可能与其他传染病有关。