Tuberculosis Infection and Genetic Variation

描述（由申请人提供）：这个K23奖将为Horne博士提供一个机会，让他在以患者为导向的临床研究中发展先天免疫遗传变异和结核病（TB）感染易感性。这一职业发展申请描述了一个全面的计划，以实现以下目标：1)组建一个患者队列，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)了解暴露于结核分枝杆菌（MTb）后的宿主先天免疫反应；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、说教式的课程作业、实际实验室技能的指导以及参加科学会议来实现。我们将在华盛顿州西雅图收集一组已知结核病暴露的患者，其具体目的如下：1)彻底表征临床和暴露相关因素，从指标病例中确定结核分枝杆菌系统发育谱系，并利用这些因素建立结核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的单核苷酸多态性（snp）是否与结核病感染有关。在我们的遗传关联分析中，我们将根据Aim 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。我们将在先前收集的以家庭为基础的队列中确认遗传关联。这项研究对于结核感染的结果和结核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、结核分枝杆菌系统遗传学、遗传流行病学、生物统计学、风险因素建模和结核传播方面的专业知识。霍恩博士是主要的导师，在先天免疫，特别是病原体识别受体和相关途径方面是一位成功和公认的专家。他在功能和遗传关联研究中研究了toll样受体（TLRs）在分枝杆菌感染中的作用。Peter Small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，对宿主遗传和对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，这项研究的结果可能对结核病疫苗的开发很重要。研究结果也可能与其他传染病有关。

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.