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: 10311896
• 负责人: Laurie Ann Rumker
• 金额: $ 3.81万
• 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/10311896
• 关键词: Characterizing; Genomic; Basis; Immune; Mediated

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)仍然是全球主要的传染病致死原因。理解 为什么一些患者出现早期症状，而另一些患者则出现潜伏感染，这对抗击 这种病。虽然已知环境因素会增加早期进展的风险，但最近的一项基因组 广联研究表明，宿主遗传因素也起到了作用，具有早期进展遗传能力 接近20%。然而，专注于欧洲人的结核病遗传学研究一直在该领域占据主导地位，受到 连锁不平衡掩盖了因果基因，并且没有集中在结核病最严重的人群上。通过 相比之下，该项目将关注来自秘鲁利马的人口，他们的结核病负担很高，有混血血统， 这将揭示更广泛的遗传变异，并使更具体的影响基因定位成为可能。早些时候 进展风险可能由免疫反应决定，免疫反应是主要的宿主-病原体界面。因此， 将单核细胞(批量)和T细胞(作为单个细胞)的转录图谱与基因分型相结合 和环境协变量数据，该项目的目标是表征由 影响结核病进展风险的基因组背景。具体地说，这个项目将：目的1)识别基因 受遗传血统影响的表达免疫表型，目的2)创建一种新的单细胞分析 方法并用它来鉴定受遗传祖先影响的细胞群体免疫表型，目的3) 确定改变免疫表型和影响结核病进展风险的特定基因组变异。如果成功， 这项工作将阐明影响结核病感染结局的基因组机制，并加深我们对 在秘鲁人群中的免疫生理学。关于阻止早期进展的遗传因素的知识 可以为治疗和疫苗的发展提供信息。这项工作还将产生一种强大的方法来 单细胞数据集中的关联性测试，协变邻域分析，可以很好地定义 其丰度因感兴趣的临床表型而改变的细胞群体的灵活性和粒度。 通过奖学金培训计划，申请者将发展：复杂性状遗传学方面的专业知识， 流利地应用和开发生物信息学方法，了解如何 环境因素也会导致传染病的结果，以及对免疫的熟悉程度 传染病管理的生理学和临床方面。理想的贴身训练环境 免疫介导性疾病的复杂性状遗传学和单细胞方法专家的指导 发展，加上具有互补科学专业知识和职业生涯的顾问网络的支持 在学术医学方面的经验，再加上参加相关的课程和会议，将会 使申请者在这个学习项目中茁壮成长。在此奖学金结束时，申请者将是 准备解决计算免疫遗传学中的关键问题，并将其应用于传染病 和全球健康，并通过学术医学的职业生涯在临床和计算世界之间架起一座桥梁。