Innate Immune Responses in Obliterative Bronchiolitis

描述(由申请人提供)： 斯科特·M·帕尔默博士，目前在杜克大学肺科任教 该部门作为医学助理，计划有计划地进行五年的职业生涯 发展计划，以便发展成为一名独立的调查员 肺内科。该提案涉及一项严格的研究培训 经验丰富的内科科学家导师大卫·施瓦茨博士，他拥有专业知识 在先天免疫的免疫遗传学中。进一步的研究培训是 建议在具有统计专业知识的共同导师的指导下提出 遗传学，一家在移植免疫学方面拥有专业知识的合作者，以及 辅以讲授的研究生课程。该计划的总体目标 拟议的研究是为了了解先天免疫反应如何有助于 移植后闭塞性毛细支气管炎综合征(BOS)的发展我们 假设先天的遗传、生理或生物差异 免疫反应性将显著改变发展为 肺移植后的BOS。这一新的假设在临床上是相关的 关于移植后死于BOS的高死亡率，科学相关 由于对BOS的病理生理学认识不完全，以及 有几个基本和临床观察支持。我们和其他人有 最近证明先天免疫存在显著的多态性。 受体基因，这些差异显著改变了随后的 炎症和免疫反应。为了检验我们的假设，我们将 研究供体和受体Toll样受体-2(TLR2)基因的多态性， TLR4、CD14基因和表型表征呼吸道生理学 120例肺移植患者对内毒素的生物学反应 收件人。我们将前瞻性地获取队列的临床信息 并确定先天遗传、生理或 BOS发生发展的生物学因素多因素分析 模特。在职业发展奖结束时，帕尔默博士将 已经在研究设计、基础遗传分析方面获得了相当多的专业知识， 移植免疫学和统计分析。他将运用这些技能 指导未来以患者为中心的研究问题的调查 肺内科。

DESCRIPTION (provided by applicant): Dr. Scott M. Palmer, currently on faculty in the Duke University Pulmonary Division as an Associate in Medicine, proposes a structured five-year career development plan in order to develop into an independent investigator in pulmonary medicine. The proposal involves rigorous research training under an experienced physician scientist mentor, Dr. David Schwartz, who has expertise in the immunogenetics of innate immunity. Further research training is proposed under the guidance of a co-mentor with expertise in statistical genetics, a collaborator with expertise in transplant immunology, and complemented by didactic graduate coursework. The overall goal of the proposed research is to understand how innate immune responses contribute to the development of posttransplant bronchiolitis obliterans syndrome (BOS). We hypothesize that genetic, physiological or biological differences in innate immune responsiveness will significantly alter the risk for the development of BOS after lung transplant. This novel hypothesis is clinically relevant based on the high rate of posttransplant death due to BOS, scientifically relevant because of the incomplete understanding of the pathophysiology of BOS, and supported by several basic and clinical observations. We and others have recently demonstrated that significant polymorphisms exist in innate immune receptor genes, and that these differences significantly alter subsequent inflammatory and immune responses. In order to test our hypothesis, we will characterize polymorphisms in donor and recipient toll-like receptor-2 (TLR2), TLR4, and CD14 genes, and phenotypically characterize the airway physiological and biological response to endotoxin in a cohort of 120 lung transplant recipients. We will prospectively capture clinical information on the cohort and determine the predictive importance of innate genetic, physiological, or biological factors on the development or progression of BOS in a multivariate model. At the conclusion of the career development award, Dr. Palmer will have gained considerable expertise in study design, basic genetic analyses, transplant immunology, and statistical analyses. He will apply these skills to direct future investigations of patient oriented research problems in pulmonary medicine.