Tuberculosis Infection and Genetic Variation

描述(申请人提供)：这项K23奖项将为霍恩博士提供一个机会，让他在以患者为导向的先天免疫遗传变异和结核病(TB)感染易感性的临床研究中发展成为一名独立的研究员。这项职业发展申请描述了一项全面的计划，以实现以下目标：1)召集患者队列，以确定结核病感染的遗传、暴露和病原体相关风险因素；2)发展宿主遗传变异和结核病感染方面的专业知识；3)发展对暴露于结核分枝杆菌(MTB)后的宿主先天性免疫反应的了解；以及4)发展独立的临床研究事业。这些目标将通过关键人员的指导、教学课程工作、实验室实用技能指导和参与科学会议来实现。我们将汇集华盛顿州西雅图的一组已知接触过结核病的患者，他们的具体目标如下：1)彻底表征临床和暴露相关因素，从指示病例中确定结核分枝杆菌的系统发生谱系，并利用这些因素建立结核病感染的风险因素模型；以及2)在无关受试者中进行嵌套病例对照研究，以确定与先天性免疫相关的候选基因中的单核苷酸多态(SNPs)是否与结核病感染有关。在我们的遗传关联分析中，我们将调整AIM 1中确定的重大临床、暴露和病原体相关风险因素。我们将确认先前收集的基于家族的队列中的遗传关联。这项研究对于结核病感染的结局和结核分枝杆菌血统的纳入是新的。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、结核分枝杆菌系统发生学、遗传流行病学、生物统计学、风险因素建模和结核病传播方面的专业知识。霍恩博士是这项研究的主要导师，他是一位成功的、公认的先天免疫专家，尤其是病原体识别受体及其相关途径。他在功能和遗传相关性研究中研究了Toll样受体(TLRs)在分枝杆菌感染中的作用。共同导师彼得·斯莫尔博士是国际公认的结核分枝杆菌系统发育专家。与结核病相比，结核病感染是一个研究不足的领域，对宿主遗传学和结核病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，这项研究的发现可能对结核病疫苗的开发具有重要意义。这一发现也可能与其他传染病相关。

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.