Human Genetics and Clinical Studies

人类遗传学和临床研究

基本信息

批准号：
10219086
负责人：
CHRISTOPHER M SASSETTI
金额：
$ 42.42万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-05 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219086
关键词：
Adult Age BCG Vaccine Bacille Calmette-Guerin vaccination CRISPR/Cas technology Candidate Disease Gene Case-Control Studies Cell Line Cell physiology Child Childhood Clinical Clinical Research Clinical Trials Coupled DNA Data Dendritic Cells Diagnosis Disease Epidemiologist Gene Deletion Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Genotype Goals Host Defense Human Human Genetics Immune Response Genes Immune response Immunologic Receptors Immunologics Immunologist Individual Infant Infrastructure Measures Mediating Meningeal Mus Mycobacterium tuberculosis Natural Immunity Pathway interactions Phylogenetic Analysis Predisposition Prospective Studies Pulmonary Tuberculosis Randomized Research Personnel Role Sampling Single Nucleotide Polymorphism Site South Africa South African Susceptibility Gene System T cell response Toll-Like Receptor Pathway Tuberculosis Tuberculosis Vaccines Vaccination Vaccines Validation Variant Vietnam Work adaptive immune response antimicrobial case control cohort control trial cytokine genetic variant genome wide association study in vivo macrophage multidisciplinary pathogen peripheral blood protein function response vaccine evaluation vaccine response whole genome

项目摘要

Abstract This core will facilitate the validation of mouse data in human cohorts through interactions with each project and by pursuing the characterization of human BCG responses and susceptibility to TB disease. The primary goal is to understand how human genetic variation regulates macrophage immune responses to Mtb infection, in vivo T-cell responses to BCG vaccination, Mtb strain type associations with pulmonary TB, and overall clinical susceptibility to TB. Over the past 10 years in Seattle, we used genetic studies to discover and characterize common human Toll-like Receptor (TLR) pathway polymorphisms which regulate macrophage and dendritic cell cytokine secretion and other host-defense pathways. Similar to gene deletion studies in mice, these au naturel polymorphisms enable us to examine deficiencies of human innate immunity genes and assess their role in ex vivo cellular function, in vivo vaccine T-cell responses, and clinical susceptibility to TB disease. In Core B, we will examine candidate TB susceptibility genes identified in Projects 1 to 3. We will determine whether candidate mouse TB susceptibility genes contain DNA variants which are functional and control replication of MTb in infected macrophages. Using a candidate gene case-control study, determine whether mouse TB susceptibility genes are associated with susceptibility to adult pulmonary TB disease in Vietnam, BCG-induced T-cell responses in South Africa, and/or pediatric TB disease in South Africa. We hypothesize that selected DNA variants in candidate TB susceptibility genes are associated with TB disease and BCG vaccine responses, control gene expression and/or protein function and mediate an effective anti- microbial macrophage response to Mtb infection. With a multidisciplinary team of epidemiologists, geneticists, and immunologists with over 10 years of collaborative work together, we propose to couple genetic and cellular analysis of Mtb-infected human macrophages and human clinical cohorts to discover the mechanisms of how common human genetic variation regulates BCG-induced immune responses and susceptibility to TB.

抽象的该核心将通过与每个项目的交互来促进人类群体中小鼠数据的验证并研究人类卡介苗反应和对结核病易感性的特征。初级目标是了解人类遗传变异如何调节巨噬细胞对结核分枝杆菌感染的免疫反应，体内 T 细胞对卡介苗疫苗的反应、结核分枝杆菌菌株类型与肺结核的关联以及总体情况结核病的临床易感性。过去 10 年在西雅图，我们利用基因研究发现并表征调节巨噬细胞的常见人类 Toll 样受体 (TLR) 通路多态性和树突状细胞细胞因子分泌和其他宿主防御途径。类似于基因缺失研究在小鼠中，这些天然的多态性使我们能够检查人类先天免疫基因的缺陷，并评估它们在离体细胞功能、体内疫苗 T 细胞反应和结核病临床易感性中的作用疾病。在核心 B 中，我们将检查项目 1 至 3 中确定的候选结核病易感基因。确定候选小鼠结核病易感基因是否含有具有功能性且有效的 DNA 变异体控制受感染巨噬细胞中 MTb 的复制。使用候选基因病例对照研究，确定小鼠结核病易感基因是否与成人肺结核病的易感性相关越南、南非卡介苗诱导的 T 细胞反应和/或南非儿童结核病。我们假设候选结核病易感基因中选定的 DNA 变异与结核病相关和卡介苗疫苗反应，控制基因表达和/或蛋白质功能并介导有效的抗- 微生物巨噬细胞对 Mtb 感染的反应。拥有一支由流行病学家、遗传学家组成的多学科团队，和免疫学家一起工作了 10 多年，我们建议将遗传和细胞结合起来分析 Mtb 感染的人类巨噬细胞和人类临床队列，以发现其机制常见的人类遗传变异调节卡介苗诱导的免疫反应和结核病易感性。