Tuberculosis Infection and Genetic Variation

结核感染和基因变异

• 批准号: 8039227
• 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/8039227
• 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奖将为Horne博士提供一个独立研究者在以患者为导向的临床研究中发展的机会，该研究对先天免疫和结核病易感性（TB）感染的遗传变异。这项职业发展申请描述了实现以下目标的全面计划：1）组装一组患者，以确定结核病感染的遗传，暴露和病原体相关的危险因素，2）在宿主遗传变异和结核病感染方面发展专业知识，3）对宿主对宿主的免疫反应的理解在暴露于mycobactium clastium teberiss的情况下，并创建了一个独立的临床研究（MT）。这些目标将通过关键人员，教学课程工作，实践实验室技能的指导以及参与科学会议来实现这些目标。我们将在华盛顿的西雅图组装一群患者，他们的结核病暴露与以下特定目的：1）完全表征与临床和暴露有关的因素，从指数案例中鉴定MTB系统发育谱系，并使用这些因素来开发TB感染的风险因素模型； 2）对无关的受试者进行嵌套的病例对照研究，以确定与先天免疫有关的候选基因中的单核苷酸多态性（SNP）是否与结核病感染有关。在我们对遗传关联的分析中，我们将调整AIM 1中确定的重要临床，暴露和与病原体相关的危险因素。我们将确认先前收集的基于家庭的队列中的遗传关联。这项研究是TB感染结果和MTB谱系纳入的新颖新颖的。华盛顿大学的丰富学术环境非常适合霍恩博士的培训，并允许他组建一个咨询委员会，其成员具有先天免疫学，MTB系统发育学，遗传流行病学，生物统计学，风险因素建模和TB传播方面的专业知识。主要导师Hawn博士是先天免疫的成功且公认的专家，尤其是病原体识别受体和相关途径。他已经研究了Toll样受体（TLR）在分枝杆菌感染中的作用在功能和遗传关联研究中。院长Peter Small博士是MTB系统发育学方面的国际公认专家。 /相关性结核病感染与结核病疾病相比是一个研究的区域，对宿主遗传学和对结核病感染的易感性知之甚少。据估计，结核病会感染全球人口的三分之一，这项研究的发现对于结核病疫苗的开发可能很重要。发现也可能与其他传染病有关。