Characterizing the Genomic Basis of Immune-Mediated Resilience Against Tuberculosis in an Admixed Peruvian Population

秘鲁混合人群中免疫介导的结核病恢复力的基因组基础特征

• 批准号: 10687191
• 负责人: Laurie Ann Rumker
• 金额: $ 5.27万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687191
• 关键词: Accounting; African ancestry; Automobile Driving; Bioinformatics; Cause of Death; Cells; Cessation of life; Clinical; Communicable Diseases; Complex Genetic Trait; Data; Data Set; Development; Disease; Disease Management; Disease Outcome; Environment; Environmental Risk Factor; European; European ancestry; Exposure to; Familiarity; Fellowship; Flow Cytometry; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic study; Genomics; Genotype; Haplotypes; Heritability; Immune; Immune response; Individual; Infection; Infectious Agent; Inflammatory; Knowledge; Light; Link; Linkage Disequilibrium; Maps; Mediating; Mediation; Medicine; Mentorship; Messenger RNA; Methodology; Methods; National Institute of Allergy and Infectious Disease; Neighborhoods; Outcome; Pathway interactions; Patients; Persons; Peru; Peruvian; Phenotype; Physiology; Population; Research; Risk; Source; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; Tuberculosis; Vaccines; Validation; Variant; Work; career; cell type; clinical phenotype; cohort; differential expression; experience; flexibility; genetic variant; genome wide association study; genotyped patients; global health; immune function; immunoregulation; improved; interest; latent infection; mRNA sequencing; meetings; method development; monocyte; novel; pathogen; power analysis; prevent; programs; progression risk; resilience; simulation; single cell analysis; social factors; therapeutic development; transcriptome; vaccine strategy

Project Summary/Abstract Tuberculosis (TB) remains the global leading cause of death from an infectious agent. Understanding why some patients present with early symptoms while others develop latent infections is critical for combating this illness. While environmental factors are known to elevate the risk of early progression, a recent Genome Wide Association Study revealed that host genetic factors also play a role, with early progression heritability near 20%. However, TB genetics studies focusing on Europeans, which have dominated the field, suffer from linkage disequilibrium obscuring causal loci and fail to center on the populations who suffer most from TB. By contrast, this project will focus on a population from Lima, Peru with high TB burden and admixed ancestry, which will reveal a broader range of genetic variants and enable more specific mapping of impactful loci. Early progression risk is likely dictated by the immune response, the primary host-pathogen interface. Therefore, using transcriptional profiling of monocytes (in bulk) and T cells (as single cells) in combination with genotyping and environmental covariate data, the objective of this project is to characterize immune phenotypes altered by genomic background that influence TB progression risk. Specifically, this project will: Aim 1) identify gene expression immune phenotypes influenced by genetic ancestry, Aim 2) create a novel single-cell analysis method and use it to identify cell population immune phenotypes influenced by genetic ancestry, and Aim 3) identify specific genomic variants that alter immune phenotypes and impact TB progression risk. If successful, this work will elucidate genomic mechanisms influencing TB infection outcomes and deepen our understanding of immune physiology in a Peruvian population. Knowledge of genetic factors that prevent early progression can inform the development of therapeutics and vaccines. This work will also produce a powerful method for association testing in single cell datasets, Covarying Neighborhood Analysis, that can define with great flexibility and granularity cell populations whose abundance is altered by a clinical phenotype of interest. Through the fellowship training plan, the applicant will develop: expertise in complex trait genetics, fluency in the application of and development of bioinformatic methodologies, an understanding of how social and environmental factors also contribute to infectious disease outcomes, and familiarity with immune physiology and clinical aspects of infectious disease management. An ideal training environment of close mentorship by an expert in complex trait genetics of immune-mediated diseases and single-cell methods development, plus support from a network of advisors with complementary scientific expertise and career experience in academic medicine, in combination with exposure to relevant coursework and meetings, will enable the applicant to thrive in this program of study. At the conclusion of this fellowship, the applicant will be poised to tackle critical problems in computational immune genetics with applications to infectious diseases and global health, and to bridge the clinical and computational worlds through a career in academic medicine.

项目摘要/摘要 结核病（TB）仍然是传染剂的全球主要死亡原因。理解 为什么有些患者出现早期症状而另一些患者会出现潜在感染对于打击至关重要 这种疾病。虽然已知环境因素可以提高早期进展的风险，但最近的基因组 广泛的关联研究表明，宿主遗传因素也起作用，具有早期进展的遗传力 接近20％。但是，关注欧洲人的结核病遗传学研究占据了领域的主导地位 连锁不平衡掩盖了因果基因座，无法以最大的结核病为中心。经过 相反，该项目将集中于秘鲁利马市的人口，具有高结核病负担，并充满了血统， 这将揭示更广泛的遗传变异，并能够对有影响力的基因座进行更具体的映射。早期的 进展风险可能取决于免疫反应，即主要的宿主 - 病原体界面。所以， 使用单核细胞（散装）和T细胞（作为单个细胞）的转录分析与基因分型结合 和环境协变量数据，该项目的目的是表征由免疫表型改变的。 影响结核病进展风险的基因组背景。具体而言，该项目将：目标1）识别基因 表达免疫表型受遗传血统影响，目标2）创建新型的单细胞分析 方法并使用它来识别受遗传血统影响的细胞群体免疫表型，并瞄准3） 确定改变免疫表型并影响结核病进展风险的特定基因组变体。如果成功， 这项工作将阐明影响结核病感染结果的基因组机制，并加深我们的理解 秘鲁人群中的免疫生理学。了解预防早期进展的遗传因素 可以告知治疗剂和疫苗的开发。这项工作还将为 在单细胞数据集中进行的关联测试，协方差分析，可以很好地定义 灵活性和粒度细胞种群的丰度会因感兴趣的临床表型而改变。 通过奖学金培训计划，申请人将发展：复杂性状遗传学方面的专业知识， 生物信息学方法论的应用和开发的流利性，对社会方式的理解 环境因素也有助于感染性疾病结果，并熟悉免疫 传染病管理的生理和临床方面。接近的理想培训环境 免疫介导疾病和单细胞方法的复杂性状遗传学专家的指导 开发，以及具有互补科学专业知识和职业的顾问网络的支持 学术医学的经验，结合接触相关的课程和会议，将 使申请人能够在此研究计划中蓬勃发展。在该奖学金结束时，申请人将是 准备解决用于传染病的计算免疫遗传学中的关键问题 和全球健康，并通过学术医学职业弥合临床和计算世界。