Sexual dimorphism in susceptibility to emphysematous tissue injury

肺气肿组织损伤易感性的性别二态性

基本信息

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
项目类别：
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

项目摘要

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）是世界范围内的一种主要慢性疾病，导致严重的慢性阻塞性肺疾病。仅凭医疗保健利用率、发病率和死亡率即可确定诊断。然而，COPD 的诊断包括多种肺部疾病。过去的研究表明，性可能会显着影响慢性阻塞性肺病（COPD）的一种形式——肺气肿（EM）。然而，我们对性二态性如何驱动还没有明确的机制理解。我们的初步研究发现，吸烟者的肺组织损伤来自 EM。与肺气肿组织高度相关的加权基因相关网络分析（WGCNA）这些 Green 模块基因在单核细胞中显着表达。谱系细胞的性别差异与肺单核细胞/巨噬细胞簇的变化显着相关。与多种族研究合作进行的一项初步研究中进行了组织单细胞 RNA 测序 (scRNA-seq)。动脉粥样硬化 (MESA) 的结果显示，1,346 名受试者的胸部 CT 发现肺气肿严重程度显着这些已完成的研究使我们采取了这种性别。差异导致男性在长期吸烟期间更容易发生肺气肿性肺损伤通过改变富含绿色模块基因的单核细胞簇来减少烟雾暴露的主要目标。这项研究旨在确定驱动单核细胞谱系不同变化的性别依赖性生物分子因素我们还将确定单核细胞在肺气肿性肺组织损伤过程中如何发生变化。谱系细胞引起肺结构（上皮和内皮）的病理学为了实现这些目标，我们。 (1). 目标 1 - 确定单核细胞谱系细胞的组成、分化、功能和使用“Green”模块作为靶基因，研究它们对肺泡上皮和内皮的下游影响设置在 C57B/6 小鼠模型中，长期暴露于香烟烟雾中，雌性或雄性的增加或减少 (2). 目标 2 - 确定肺中单核细胞谱系细胞组成之间的相关性。 UVa 队列的 scRNA-seq 和胸部 CT 得出的肺气肿严重程度在性别和存在或不存在方面保持平衡使用“Green”模块作为目标基因组的 COPD (n=60) 目标 3 - 测试 Green 模块作为目标基因集。纵向 MESA 检查肺气肿演变过程中性别二态性的纵向中介 5 至检查 6。肺气肿主要对除肺减容策略和治疗之外的所有可用疗法均具有抵抗力。迄今为止，人们对肺中单核细胞的功能知之甚少。因此，我们的建议可以提供关键的生物分子信息。女性和男性之间的风险评估，识别失调的过程，并帮助制定策略通过性别二态性和单核细胞生物学来减轻和治疗肺气肿性慢性阻塞性肺病。