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，是第三大主要原因 在美国的死亡。值得注意的是，有相似吸烟史的人有不同的易感性 本病发生发展，患者表现出不同程度的临床表现。遗传因素可能 解释了这些差异，但变异的功能、细胞和分子基础仍有待于 探索过了。该项目旨在连接COPD全基因组关联研究(GWAS)中的知识 通过观察：(1)炎性反应 是香烟烟雾暴露最显著的差异之一；(2)基于遗传动物模型 对慢性阻塞性肺疾病严重炎症反应的显著特征进行了总结。 具体地说，我们发现遗传小鼠模型缺乏Hedgehog相互作用蛋白(HHIP)，一种基因 在GWAS中持续与COPD相关，不仅概括了强大的肺气肿易感性，而且显示 一种类似于人类慢性阻塞性肺疾病的强烈炎症表型。特别是，激活的CD8+T细胞的增加是 在肺气肿发展过程中观察到的。单细胞RNA测序的初步研究 研究表明，HHIP的表达仅限于肺成纤维细胞，而在免疫细胞中缺失，包括 淋巴细胞。此外，HHIP缺陷的肺成纤维细胞增加了已知激活的细胞因子的表达。 CD8+T细胞。这些发现导致我们假设，肺成纤维细胞中HHIP表达减少会导致 细胞因子的增加和CD8+T细胞的激活，而这些激活的CD8+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CD8+T细胞的激活是否依赖于HHIP；2.确定CD8+T细胞的功能 HHIP缺乏诱导淋巴细胞活化在吸烟所致肺部炎症中的重要性 确定人类HHIP危险基因与肺淋巴细胞炎的关系 研究对象。 云博士将在慢性阻塞性肺疾病基因组学领域的专家赫什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慢性阻塞性肺病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咨询委员会的指导下， 与这项提案的关键领域有关的专门知识，包括肺部免疫学、功能验证和生物统计学， 云博士制定了一个全面的五年培训计划。这一K08奖项将支持云博士 培养成为一名独立的内科医生-科学家所需的技能，并以理解为长期目标 基因变异如何通过连接人类组学数据和候选基因的功能验证来修改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.