Demographics Causes and Consequences of B Cell Repertoire Diversity

B 细胞库多样性的人口统计学原因和后果

• 批准号: 9199843
• 负责人: Ramy Arnaout
• 金额: $ 19.14万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199843
• 关键词: Address; Affect; Age; Aging; Antibodies; Antibody Diversity; Antibody titer measurement; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biology; Biomedical Research; CD19 gene; Cell Survival; Cell physiology; Cells; Cessation of life; Chad; Characteristics; Chlamydophila pneumoniae; Chronic; Chronology; Clinical; Clinical Microbiology; Complement; Cytomegalovirus; Data; Elderly; Epidemiologic Methods; Epidemiologist; Epidemiology; Foundations; Funding; Future; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Goals; Grant; Health; Helicobacter pylori; Herpesvirus 1; High-Throughput Nucleotide Sequencing; Home environment; Human; Hypersensitivity; Immune; Immune response; Immunity; Immunology; Impairment; Infection; Infectious Agent; Inflammation; Institutes; Institution; Interleukin-1; Interleukin-6; Israel; Longitudinal cohort study; Malignant Neoplasms; Mathematics; Measures; Medical center; Medicine; Mentors; Mentorship; Multi-Ethnic Study of Atherosclerosis; Mus; Outcome; Pathologist; Pathology; Patients; Peritoneal; Persons; Play; Population; Principal Component Analysis; Principal Investigator; Program Development; Public Health Schools; Publications; Reaction; Research; Research Personnel; Resources; Risk; Role; Running; Sampling; Serum; Signal Transduction; Signaling Protein; Structure; Suggestion; Systems Biology; T cell response; TNF gene; Testing; Training; Transfusion; Transplantation; United States National Institutes of Health; Universities; V(D)J Recombination; Vaccination; Vaccines; Variant; Vermont; Washington; Work; aging population; base; career; career development; cohort; demographics; falls; genetic association; genetic epidemiology; genome analysis; genome sequencing; genome wide association study; indexing; inflammatory marker; mathematical methods; mid-career faculty; mortality; population health; professor; programs; public health relevance; skills

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.

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，其目标是让 Ramy Arnaout 做好准备，成为群体免疫学领域完全独立的研究者。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，并作为一名临床病理学家，提供流行病学方面的专业知识。主要指导将由三名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 博士的所在机构）医学副教授，流行病学专家； Bruce Psaty，华盛顿大学流行病学教授、全基因组关联专家；佛蒙特大学病理学教授 Russell Tracy 是免疫纵向队列研究专家。他们将由免疫学专家（怀特海研究所免疫学教授 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席主任查德·努斯鲍姆）作为顾问加入。培训计划包括该团队的结构化指导、哈佛大学公共卫生学院流行病学的正式课程以及提供全面流行病学培训的研究计划。在他的初步研究中，Arnaout 博士开发了一个用于 B 细胞库的高通量测序和表征的流程，重点关注 V(D)J 重组抗体重链基因。他通过对人类和小鼠的全部序列进行测序来证明了这一流程，这是第一作者的出版物。然后，他开发了一种研究谱多样性的数学方法，并通过表征具有不寻常多样性特征的小鼠腹膜 B-1a 细胞的谱多样性以及通过在开发 B-1a 细胞中非基于抗原的选择的惊人发现来证明其实用性。 -小鼠的细胞亚群。在当前的提案中，Arnaout 博士将在这项工作的基础上，将他的管道应用于大量人群（来自广泛使用、数据丰富的 NIH 资助的动脉粥样硬化多种族研究 (MESA) 的 1,000 名患者），以研究B 细胞库多样性的人口统计、原因和后果。他将使用他已获准访问的 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原滴度的横截面关联； (ii) B 细胞多样性指标与总死亡率的纵向关联； (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 重组机制的基因中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，以及对感染和疫苗接种的影响。随着 Arnaout 博士在流行病学领域实现完全独立，这项工作将为未来研究 B 细胞库在人口健康中的作用奠定基础。