Demographics Causes and Consequences of B Cell Repertoire Diversity

描述（由申请人提供）：该提案描述了一个为期五年的职业发展计划，其目标是为Ramy Arnaout成为一名完全独立的人群免疫学研究者做好准备。该项目将以Arnaout博士在免疫学、数学和基因组学方面的背景为基础，并通过提供流行病学方面的专业知识作为临床病理学家。主要指导将由三个导师组成的团队提供：博士。Kenneth Mukamal，贝斯以色列女执事医疗中心（BIDMC； Arnaout博士的家庭机构）的医学副教授，流行病专家；华盛顿大学流行病学教授、全基因组关联专家Bruce Psaty；以及佛蒙特大学病理学教授、免疫纵向队列研究专家拉塞尔·特雷西（Russell Tracy）。他们将由免疫学专家（海德研究所免疫学教授Hidde Ploegh）和基因组学专家（布罗德研究所基因组测序和分析项目联合主任Chad Nusbaum）作为顾问加入。培训计划包括由该小组提供有组织的指导，哈佛大学公共卫生学院的正式流行病学课程，以及提供流行病学全面培训的研究项目。在他的初步研究中，Arnaout博士开发了一个高通量测序和b细胞谱表征的管道，重点是V(D) j重组抗体重链基因。他以第一作者的身份发表文章，通过对人类和老鼠的基因库进行测序，证明了这一管道。然后，他开发了一种研究库多样性的数学方法，并通过描述具有不同寻常多样性特征的小鼠腹膜B-1a细胞的库多样性，以及通过在小鼠发育中的b细胞亚群中发现非抗原选择的惊人发现，证明了其实用性。在目前的提案中，Arnaout博士将在这项工作的基础上，将他的管道应用到一个大的人群中——从广泛使用的、数据丰富的nih资助的动脉粥样硬化多种族研究（MESA）中抽取1000名患者——研究b细胞库多样性的人口统计学、原因和后果。他将使用MESA的样本和数据（他已获得访问权）来测试(i) b细胞多样性测量与年龄和各种感染因子滴度的横断面关联；（ii） b细胞多样性测量与总死亡率的纵向关联；（iii） b细胞多样性测量与VH、D和JH基因片段以及编码V(D)J重组机制的基因的种系变异之间的遗传关联。因此，他将发现b细胞库在人群中如何变化的基本特征，这对感染和疫苗接种具有重要意义。这项工作将为未来研究b细胞在人群健康中的作用提供基础，因为Arnaout博士在流行病学方面实现了完全的独立。

DESCRIPTION (provided by applicant): This proposal describes a five-year career development program whose goal is to prepare Ramy Arnaout for a role as a fully independent investigator in population immunology. This program will build on Dr. Arnaout's background in immunology, mathematics, and genomics and as a clinical pathologist by providing expertise in epidemiology. The principal guidance will be provided by a team of three mentors: Drs. Kenneth Mukamal, Associate Professor of Medicine at the Beth Israel Deaconess Medical Center (BIDMC; Dr. Arnaout's home institution), an expert epidemiologist; Bruce Psaty, Professor of Epidemiology at the University of Washington and an expert in genome-wide association; and Russell Tracy, Professor of Pathology at the University of Vermont, an expert in longitudinal cohort studies of immunity. They will be joined by experts in immunology (Hidde Ploegh, Professor Immunology at the Whitehead Institute) and genomics (Chad Nusbaum, co-director of the Genome Sequencing and Analysis program at the Broad Institute) as consultants. The training plan includes structured mentorship by this team, formal coursework in epidemiology at the Harvard School of Public Health, and a research program that will provide thorough training in epidemiology. In his preliminary studies, Dr. Arnaout has developed a pipeline for the high-throughput sequencing and characterization of B-cell repertoires, with a focus on V(D)J-recombined antibody heavy-chain genes. He has demonstrated this pipeline by sequencing repertoires of both humans and mice, a first-author publication. He then developed a mathematical approach for investigating repertoire diversity, and demonstrated its utility both by characterizing the repertoire diversity of murine peritoneal B-1a cells, which have unusual diversity characteristics, and via the surprising discovery of non-antigen-based selection in developing B-cell subsets in mice. In the current proposal, Dr. Arnaout will build on this work by applying his pipeline to a large human population-1,000 patients drawn from the widely used, data-rich NIH-funded Multi-Ethnic Study of Atherosclerosis (MESA)-to study the demographics, causes, and consequences of B-cell repertoire diversity. He will use samples and data from MESA, to which he has been granted access, to test (i) the cross-sectional association of B-cell diversity measures with age and with titers of various infectious agents; (ii) the longitudinal association of B-cell diversity measures with total mortality; and (iii) the genetic association between B-cell diversity measures and germline variation in VH, D, and JH gene segments and in the genes that encode the V(D)J recombination machinery. He will thereby discover the fundamental features of how B-cell repertoires vary in the population, with implications for infection and vaccination. This work will provide a foundation for future studies on the role of B-cell repertoires in population health as Dr. Arnaout achieves full independence in epidemiology.