Sexual dimorphism in susceptibility to emphysematous tissue injury

肺气肿组织损伤易感性的性别二态性

• 批准号: 10736224
• 负责人: ANI Wang MANICHAIKUL
• 金额: $ 77.39万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736224
• 关键词: Air; Anatomy; Award; Biological; Biological Testing; Biology; Cell Lineage; Cells; Chronic; Chronic Disease; Chronic Obstructive Pulmonary Disease; Cigarette; Collaborations; Collection; Confusion; Data; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Etiology; Evolution; Female; Future; Gene Cluster; Genes; Genetic Predisposition to Disease; Goals; Gonadal Steroid Hormones; Gonadal structure; High Prevalence; Human; Knowledge; Lung; Lung Transplantation; Lung Volume Reductions; Lung diseases; Macrophage; Mediator; Modeling; Morbidity - disease rate; Motivation; Multi-Ethnic Study of Atherosclerosis; Mus; Myeloid Cells; Ovary; Participant; Pathogenesis; Pathology; Pathway Analysis; Pattern; Play; Predisposition; Process; Pulmonary Emphysema; Pulmonary Pathology; Reporting; Resistance; Risk; Risk Assessment; Risk Behaviors; Role; Severities; Sex Differences; Smoke; Smoker; Structure; Structure of parenchyma of lung; Testing; Tissues; Visit; Work; airway obstruction; alveolar epithelium; chest computed tomography; cigarette smoke; cohort; density; exposure to cigarette smoke; follow-up; former smoker; gonad function; health care service utilization; immunomodulatory strategy; lung injury; male; monocyte; mortality; mouse model; non-smoker; novel diagnostics; novel therapeutics; sex; sexual dimorphism; single-cell RNA sequencing; tissue injury; transcriptome; transcriptome sequencing; transcriptomics

Abstract Chronic Obstructive Pulmonary Disease (COPD) is a leading chronic disease worldwide, causing significant healthcare utilization, morbidity, and mortality. Irreversible airflow obstruction alone can establish the diagnosis of COPD. However, a diagnosis of COPD includes a heterogeneous collection of lung diseases. This proposal will focus on one form of COPD, emphysema (EM). Past studies suggest that sex may significantly impact the EM severity. However, we do not have a clear mechanistic understanding of how sexual dimorphism drives smokers’ lung tissue injury toward or award from EM. Our preliminary studies identified a gene module from Weighted Gene Correlation Network Analysis (WGCNA) that highly correlated with emphysematous tissue remodeling related to sex differences. These Green module genes were significantly expressed in monocyte lineage cells. Sex differences significantly correlate with changes in monocyte/macrophage clusters of the lung tissue single-cell RNA sequencing (scRNA-seq). In a preliminary study collaborating with the Multi-Ethnic Study of Atherosclerosis (MESA), we concluded that emphysema severity in 1,346 subjects’ chest CT was significantly worse in male smokers than in female smokers. These completed studies led us to hypothesize that sex differences cause greater susceptibility for males to develop emphysematous lung injury during chronic cigarette smoke exposure by altering the monocyte clusters enriched with the Green module genes. The primary goal of this study is to identify sex-dependent biomolecular factors that drive the divergent changes in monocyte-lineage cells during emphysematous pulmonary tissue injury. We will also determine how these changes in monocyte- lineage cells cause pathology in lung structures (epithelium and endothelium). To achieve these goals, we propose three aims. (1). Aim 1 - Determine monocyte-lineage cells’ composition, differentiation, functions, and their downstream effects on the alveolar epithelium and endothelium, using the “Green” module as a target gene set in the C57B/6 murine model over chronic cigarette smoke exposure with gain or loss of female or male gonadal functions. (2). Aim 2 - Determine the correlation between monocyte-lineage cells’ composition in lung scRNA-seq and emphysema severity by chest CT from UVa cohorts balanced in sex and presence or absence of COPD (n=60) using the “Green” module as a target gene set. (3). Aim 3 - Test the Green module as a longitudinal mediator of sexual dimorphism during the evolution of emphysema from longitudinal MESA Exams 5 to Exam 6. Emphysema is mainly resistant to all available therapies except lung volume reduction strategy and lung transplant. To date, little is known about the functions of monocytes at the level of single cells in the lungs undergoing emphysematous damage. Therefore, our proposal can provide critical biomolecular information between females and males to assess the risk, identify the dysregulated processes, and help develop strategies to mitigate and treat emphysematous COPD tailored by sexual dimorphism and monocyte biology.

抽象的 慢性阻塞性肺疾病（COPD）是全世界领先的慢性疾病，导致显着 医疗保健利用，发病率和死亡率。仅凭不可逆转的气流异议就可以建立诊断 COPD。但是，对COPD的诊断包括肺部疾病的异质收集。这个建议 将专注于一种COPD，肺气肿（EM）。过去的研究表明，性可能会显着影响 严重性。但是，我们对性二态性的驱动方式没有明确的机械理解 吸烟者对EM的肺组织损伤或授予。我们的初步研究确定了一个基因模块 加权基因相关网络分析（WGCNA）与溢质组织高度相关 重塑与性别差异有关。这些绿色模块基因在单核细胞中显着表达 谱系细胞。性别差异与肺的单核细胞/巨噬细胞簇的变化显着相关 组织单细胞RNA测序（SCRNA-SEQ）。在一项与多民族研究合作的初步研究中 在动脉粥样硬化（MESA）中，我们得出结论，1,346名受试者的胸部CT的肺气肿严重程度显着 男性吸烟者比女性吸烟者更糟糕。这些完成的研究使我们假设性行为 差异会导致男性在慢性香烟期间产生杂质肺损伤的敏感性更大 通过改变富含绿色模块基因的单核细胞簇来暴露烟雾。主要目标 这项研究是为了确定依赖性的生物分子因素，这些因素驱动单核细胞分离的不同变化 肺组织损伤期间的细胞。我们还将确定单核细胞的这些变化如何 谱系细胞引起肺结构（上皮和内皮）的病理。为了实现这些目标，我们 提案三个目标。 （1）。目标1-确定单核细胞细胞的组成，分化，功能和 它们对牙槽上皮和内皮的下游影响，使用“绿色”模块作为靶基因 在C57B/6鼠模型中设置在慢性香烟烟雾暴露中，并损失女性或男性 性腺功能。 （2）。 AIM 2-确定单核细胞单位细胞在肺中的组成之间的相关性 scrna-seq和肺气肿严重程度在性别与存在或不存在的UVA队列中的胸部CT 使用“绿色”模块作为靶基因集的COPD（n = 60）。 （3）。 AIM 3-测试绿色模块作为一个 纵向MESA考试演变中性二态性的纵向介体 5至检查6。肺气肿主要抵抗所有可用的疗法，除了减少肺部量策略和 肺移植。迄今 遭受杂碎的损害。因此，我们的建议可以提供关键的生物分子信息 在女性和男性之间评估风险，确定失调过程并帮助制定策略 减轻和治疗由性二态性和单核细胞生物学量身定制的杂质COPD。