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.

摘要 慢性阻塞性肺疾病（COPD）是世界范围内的主要慢性疾病，引起严重的肺损伤。 卫生保健利用率、发病率和死亡率。仅凭不可逆的气流阻塞即可确诊 关于COPD然而，COPD的诊断包括肺部疾病的异质集合。这项建议 将集中在一种形式的慢性阻塞性肺病，肺气肿（EM）。过去的研究表明，性可能会显著影响 EM严重度。然而，我们没有一个明确的机制，了解如何性别二型驱动器， 吸烟者的肺组织损伤可能与EM有关。我们的初步研究发现了一个基因模块， 与肺气肿组织高度相关的加权基因相关网络分析（WGCNA） 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。性别差异与肺单核细胞/巨噬细胞簇的变化显著相关 组织单细胞RNA测序（scRNA-seq）。在与多民族研究合作的初步研究中， 我们的结论是，1,346名受试者的胸部CT显示肺气肿的严重程度显著高于其他受试者。 男性吸烟者比女性吸烟者更严重。这些已完成的研究使我们假设性 差异导致男性在长期吸烟期间更容易患肺气肿性肺损伤 烟雾暴露通过改变富含绿色模块基因的单核细胞簇。的首要目标 本研究旨在确定驱动单核细胞谱系分化的性别依赖性生物分子因子， 细胞在肺气肿肺组织损伤。我们还将确定单核细胞的这些变化- 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 提出三个目标。（一）.目的1 -确定单核细胞系细胞的组成，分化，功能， 利用“绿色”模块作为靶基因，研究其对肺泡上皮和内皮的下游作用 在慢性香烟烟雾暴露的C57 B/6小鼠模型中设定， 性腺功能（二）、目的2 -确定肺中单核细胞系细胞组成之间的相关性 性别和存在或不存在平衡的UVa队列的scRNA-seq和肺气肿严重程度（通过胸部CT） 使用“绿色”模块作为靶基因集，对COPD（n=60）的患者进行基因测序。（三）、目标3 -将绿色模块作为 纵向梅萨检查肺气肿演变过程中性二型性的纵向介导因子 五是考试六。肺气肿主要对除肺减容策略外的所有可用疗法具有抗性， 肺移植迄今为止，人们对肺中单核细胞在单细胞水平上的功能知之甚少 正在遭受肺气肿性损伤因此，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，确定失调的过程，并帮助制定战略， 以减轻和治疗肺气肿性COPD定制的两性异形和单核细胞生物学。