Role of B cell activating factor in non-infectious complications of common variable immunodeficiency

项目摘要 这项建议的目标是支持PI发展成为一个独立的以病人为导向的研究者 具有常见变异免疫缺陷（CVID）和B细胞生物学方面的专业知识。PI将接受所有 该计划的各个方面，并接受系统生物学方法的培训，以人类免疫学研究。 候选人-PI拥有MD和PhD学位，已完成内科住院医师培训， 过敏/免疫学奖学金在西奈山医疗中心，并已被任命为助理教授， 西奈山伊坎医学院医学系。彼已加入博士之实验室。 夏洛特Cunningham-Rundles和他的前期工作确定了CVID的免疫学特征 非感染性并发症。阐明这些并发症的发病机制是本建议的重点。 研究- CVID是最常见的症状性原发性免疫缺陷。其最大的发病率和 非感染性并发症，即自身免疫（AI）和淋巴增生（LH）导致死亡。 PI先前已详细描述了间质性肺病基础肺LH的细胞特征 (ILD)并确定了这些并发症的临床和实验室相关性。最近，PI 发现B细胞活化因子（BAFF）在CVID患者中升高，伴有进行性AI和LH， 在ILD患者的肺部局部产生。此外，BAFF受体（BAFF-R）表达和 信号传导定位于LH内的卵泡，B细胞成熟在CVID患者中最严重地被阻滞， BAFF介导AI和LH，以及持续未成熟B细胞亚群的凋亡抵抗。我们 假设AI和LH是由CVID中未成熟B细胞亚群中过量BAFF-R信号传导引起的。 职业发展-主要导师（坎宁安-伦德尔博士）是大卫S。Gottesman教授 他是西奈山的免疫学教授，也是CVID的国际权威。她管理着一个由国家卫生研究院资助的实验室， PI将基于并指导大型临床免疫学实践， 招募的共同导师Andrea Cerutti博士是通过细胞因子非依赖T细胞激活B细胞的专家 他是西奈山医学院的教授。其他咨询委员会成员包括 受人尊敬的研究人员具有不同的专业知识，将补充候选人的研究指导， 职业发展。候选人还将受益于伊坎的合作研究环境 西奈山医学院，完成生物信息学和系统生物学课程。 概要-利用重点研究方法，专家指导和战略教育计划， 该提案详细介绍了一个为期5年的培训计划，为学术生涯在初级免疫缺陷和人类 B细胞生物学在培训结束时，PI将成为一名独立的医生 在CVID、BAFF生物学和高通量人类免疫学研究方法方面具有专长的科学家。

Project Summary The goal of this proposal is to support the PI’s development into an independent patient-oriented researcher with expertise in common variable immunodeficiency (CVID) and B cell biology. The PI will be mentored in all aspects of the proposal and receive training in systems biology approaches to human immunology research. Candidate - The PI holds MD and PhD degrees, has completed internal medicine residency and allergy/immunology fellowship at Mount Sinai Medical Center, and has been appointed Assistant Professor in Department of Medicine at the Icahn School of Medicine at Mount Sinai. He has joined the laboratory of Dr. Charlotte Cunningham-Rundles and his preliminary work defined the immunological characteristics of CVID non-infectious complications. Elucidating pathogenesis of these complications is the focus of this proposal. Research – CVID is the most common symptomatic primary immunodeficiency. Its greatest morbidity and mortality results from non-infectious complications, namely autoimmunity (AI) and lymphoid hyperplasia (LH). The PI has previously detailed the cellular characteristics of pulmonary LH underlying interstitial lung disease (ILD) in these patients and defined clinical and laboratory associations of these complications. Recently, the PI found B cell activating factor (BAFF) elevated in the CVID patients with progressive AI and LH and the cytokine to be produced locally in the lungs of patients with ILD. Also, BAFF receptor (BAFF-R) expression and signaling is localized to follicles within LH, B cell maturation is most profoundly arrested in CVID patients with AI and LH, and apoptosis resistance of the persisting immature B cell subsets is mediated by BAFF. We hypothesize that AI and LH result from excessive BAFF-R signaling in immature B cell subsets in CVID. Career Development - The primary mentor (Dr. Cunningham-Rundles) is the David S. Gottesman Professor of Immunology at Mount Sinai and is an international authority on CVID. She runs the NIH-funded lab in which the PI will be based and directs the large clinical immunology practice from which study subjects will be recruited. Co-mentor Dr. Andrea Cerutti is an expert in T cell-independent activation of B cells via cytokines such as BAFF and is a Professor of Medicine at Mount Sinai. Additional advisory committee members are respected investigators with diverse expertise that will supplement the candidate’s research mentorship and career development. The candidate will also benefit from the collaborative research environment of the Icahn School of Medicine at Mount Sinai and complete coursework in bioinformatics and systems biology. Synopsis – Drawing upon a focused research approach, expert mentorship, and a strategic educational plan, this proposal details a 5 year training program for an academic career in primary immunodeficiency and human B cell biology. At the conclusion of training, the PI will be positioned to become an independent physician scientist with expertise in CVID, BAFF biology, and high throughput human immunology research methods.