The role of COPD genetic risk factor HHIP on lymphocytic inflammation

项目摘要 慢性阻塞性肺疾病（COPD），主要由吸烟引起，是第三大原因 死亡在美国。值得注意的是，具有相似吸烟史的人具有不同的易感性 发展为疾病，患者表现出不同程度的临床表现。遗传因素可能 解释这些差异，但变异的功能，细胞和分子基础仍然是 探讨了该项目旨在从COPD的全基因组关联研究（GWAS）中获得知识 疾病的病理生理机制，通过利用以下观察：（1）炎症反应 是暴露于香烟烟雾后最显著的差异之一;（2）基于遗传的动物模型 对GWAS的研究概括了COPD中严重炎症反应的突出特征。 具体地说，我们发现，遗传小鼠模型缺乏刺猬相互作用蛋白（HHIP），一个基因， 在GWAS中与COPD一致相关，不仅概括了肺气肿的易感性， 与人COPD相似的强烈炎症表型。特别是，活化的CD 8 +T细胞的增加是 沿着肺气肿发展的过程进行观察。使用单细胞RNA测序的初步研究 显示Hhip表达仅限于肺成纤维细胞，而不存在于免疫细胞，包括肺成纤维细胞。 淋巴细胞此外，Hhip缺陷型肺成纤维细胞增加了已知激活细胞因子的表达。 CD 8 +T细胞。这些发现使我们假设肺成纤维细胞中HHIP表达的减少导致了肺成纤维细胞的凋亡。 细胞因子的增加和CD 8 +T细胞的活化，这些活化的CD 8 +T细胞在 实质破坏（肺气肿）。我们建议通过以下具体目标来研究这一假设： 1.确定肺成纤维细胞中CD 8 +T细胞活化是否依赖于Hhip，2.确定函数 Hip缺乏诱导的淋巴细胞活化在烟雾诱导的肺部炎症中的重要性; 3. 人类高脂血症高血压易感基因与肺淋巴细胞炎症的关系 科目 博士Yun将在COPD基因组学领域的专家Hersh博士的指导下进行这项工作。 功能基因组学领域专家周博士和COPD遗传流行病学专家西尔弗曼博士。 在她的导师和由杰出科学家组成的科学顾问委员会的指导下， 与本提案关键领域相关的专业知识，包括肺免疫学、功能验证和生物统计学， 博士Yun制定了一个全面的五年培训计划。K 08奖将支持Yun博士 培养成为一名独立的医生-科学家所需的技能，其长期目标是了解 遗传变异如何通过桥接人类组学数据和候选者功能验证来改变COPD 基因.

Project Summary Chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoking, is the third leading cause of death in the United States. Remarkably, individuals with similar smoking histories have different susceptibility to develop the disease, and patients display a variable degree of clinical manifestations. Genetic factors may account for these differences, but the functional, cellular and molecular basis of the variation remains to be explored. This project aims to bridge knowledge from the genome-wide association studies (GWAS) of COPD to the pathophysiological mechanisms of the disease by utilizing the observations that (1) inflammatory response is one of the most prominent differences upon cigarette smoke exposure and (2) a genetic animal model based on GWAS recapitulates the prominent features of a severe inflammatory response in COPD. Specifically, we found that genetic mouse models deficient of Hedgehog interacting protein (HHIP), a gene consistently associated with COPD in GWAS, not only recapitulate robust emphysema susceptibility, but display a strong inflammatory phenotype similar to human COPD. In particular, an increase in activated CD8+T cells is observed along the course of emphysema development. Preliminary studies using single cell RNA sequencing showed that Hhip expression is restricted to lung fibroblasts and absent from immune cells including the lymphocytes. Moreover, Hhip deficient lung fibroblasts have increased expression of cytokines known to activate CD8+T cells. These findings led us to hypothesize that reduced HHIP expression in lung fibroblasts leads to an increase in cytokines and activation of CD8+T cells, and these activated CD8+T cells play a major role in parenchymal destruction (emphysema). We propose to investigate this hypothesis by the following specific aims: 1. Determine whether CD8+T cell activation depends on Hhip in lung fibroblasts, 2. Determine the functional importance of lymphocytic activation induced by Hhip-deficiency in smoke-induced lung inflammation and 3. Determine the relationships between HHIP risk locus and pulmonary lymphocytic inflammation in human subjects. Dr. Yun will perform this work under the mentorship of Dr. Hersh, an expert in the field of COPD genomics, Dr. Zhou, an expert in the field of functional genomics, and Dr. Silverman, an expert in COPD genetic epidemiology. With the guidance of her mentors and scientific advisory committee composed of distinguished scientists with expertise related to key areas of this proposal including lung immunology, functional validation and biostatistics, Dr. Yun has developed a comprehensive five-year training program. This K08 award will support Dr. Yun to develop the skills needed to become an independent physician-scientist with the long-term goal of understanding how genetic variation modifies COPD by bridging human ‘omics data and functional validation of candidate genes.