Demographics Causes and Consequences of B Cell Repertoire Diversity

描述(由申请人提供)：这份建议书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员做好准备。该计划将以阿诺特博士在免疫学、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，作为一名临床病理学家。主要指导将由三位导师组成的团队提供：贝丝以色列女执事医学中心(BIDMC；Arnaout博士的家乡机构)医学副教授Kenneth Mukamal博士，流行病学家；华盛顿大学流行病学教授和全基因组关联专家Bruce Psaty；以及佛蒙特州大学病理学教授Russell Tracy，免疫纵向队列研究专家。他们将与免疫学专家(怀特黑德研究所免疫学教授希德·普洛夫)和基因组学专家(布罗德研究所基因组测序和分析项目联席主任查德·努斯鲍姆)一起担任顾问。培训计划包括这个团队的结构化指导，哈佛公共卫生学院的流行病学正式课程，以及一个将提供全面流行病学培训的研究计划。在他的初步研究中，阿诺特博士开发了一条高通量测序和鉴定B细胞谱系的流水线，重点是V(D)J重组抗体重链基因。他通过对第一作者出版的人类和老鼠的曲目进行测序，展示了这一流水线。然后，他开发了一种研究谱系多样性的数学方法，并通过表征具有不同寻常的多样性特征的小鼠腹膜B-1a细胞的谱系多样性，以及在小鼠体内发展B细胞亚群的非基于抗原的选择的令人惊讶的发现，证明了这种方法的实用性。在目前的提案中，阿纳奥特博士将在这项工作的基础上，将他的研究渠道应用于大量人类群体--1000名患者来自广泛使用的、数据丰富的NIH资助的动脉粥样硬化多种族研究(MESA)--以研究B细胞谱系多样性的人口统计学、原因和后果。他将使用他获准访问的MESA的样本和数据来测试(I)B细胞多样性指标与年龄和各种感染源滴度的横截面关联；(Ii)B细胞多样性指标与总死亡率的纵向关联；以及(Iii)B细胞多样性指标与VH、D和JH基因片段以及编码V(D)J重组机制的基因的胚系变异之间的遗传关联。因此，他将发现B细胞谱系在人群中如何变化的基本特征，以及对感染和疫苗接种的影响。随着阿诺特博士在流行病学上实现完全独立，这项工作将为未来研究B细胞谱系在人群健康中的作用提供基础。

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.