Vasculopathy and Systemic Sclerosis-Associated Interstitial Lung Disease

血管病变和系统性硬化症相关间质性肺病

• 批准号: 10680544
• 负责人: Elana Bernstein
• 金额: $ 70.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680544
• 关键词: Adult; Affect; Alveolar; Arteries; Autopsy; Biopsy; Blood Vessels; Blood Volume; Blood capillaries; Carbon Monoxide; Cause of Death; Cells; Clinical; Clinical Trials; Data; Development; Diffusion; Endothelial Cells; Endothelium; Event; Fibrosis; Functional disorder; Goals; Hospitalization; Infection; Inflammation; Injury; Interstitial Lung Diseases; Intervention; Lung; Lung diseases; Measures; Microscopic Angioscopy; Microvascular Dysfunction; Molecular; Neoplasms; Operative Surgical Procedures; Outcome Measure; Pathogenesis; Pathway interactions; Patients; Perfusion; Peripheral; Population; Prevention; Primary Prevention; Prospective, cohort study; Regulation; Research; Secondary Prevention; Structure; Structure of parenchyma of lung; Systemic Scleroderma; Techniques; Testing; Time; Vascular Diseases; Vascular Endothelium; Vasodilator Agents; Visualization; Vital capacity; X-Ray Computed Tomography; angiogenesis; autoimmune rheumatologic disease; blood perfusion; cell injury; contrast enhanced; density; digital; early onset; fibrotic lung disease; illness length; indexing; mortality; new technology; novel; novel therapeutic intervention; peripheral blood; prevent; pulmonary function; pulmonary function decline; reactive hyperemia; response; severe injury; single-cell RNA sequencing; tonometry; transcriptome; transcriptomics; vascular endothelial dysfunction; vascular injury; vasculogenesis

Project Summary/Abstract Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease characterized by vasculopathy, inflammation, and fibrosis, and has the highest case specific mortality rate of all systemic autoimmune rheumatic diseases. Interstitial lung disease (ILD), a closely related group of lung disorders characterized by alveolar inflammation, injury, and fibrosis not due to infection or neoplasia, affects 40-60% of adults with SSc and is the primary cause of death and hospitalization in this population. Treatments for SSc-ILD are limited, and no studies have tested interventions to prevent the development of SSc-ILD. Vasculopathy is a hallmark of SSc and one of its earliest manifestations. We hypothesize that endothelial damage and microvascular injury are critical inciting events in the pathogenesis of SSc-ILD, and are therefore potential novel treatment targets for the prevention of SSc-ILD. The overarching goal of this proposal is to elucidate the relationships between the pulmonary and peripheral microvasculature, endothelial function, lung function, and ILD in adults with SSc. We will perform a prospective cohort study of 100 adults with SSc in which we will combine structural, functional, and molecular approaches to understand how the vascular compartment contributes to the development of ILD in SSc. In Aim 1, we will quantify the pulmonary microvascular perfused blood volume in SSc and SSc-ILD and determine its relationship to peripheral microvascular structure and lung function. In Aim 2, we will compare peripheral microvascular endothelial function between SSc patients with and without ILD and determine the relationship between peripheral microvascular endothelial function and pulmonary microvascular perfusion, peripheral microvascular structure, and lung function in adults with SSc. In Aim 3, we will perform single cell RNA sequencing of circulating endothelial cells to uncover the molecular mechanisms that distinguish adults with SSc from those with SSc-ILD. Our study has the potential to generate paradigm- shifting results that will (1) change the way we conceptualize the putative causal relationship between microvascular disease and ILD in SSc, (2) identify novel outcome measures for use in SSc-ILD clinical trials, and (3) enable us to develop new treatments for the primary and secondary prevention of SSc-ILD. We anticipate that the results of this study will inform and be applicable to other fibrotic lung diseases, thereby paving the way toward novel therapeutic approaches.

项目摘要/摘要 全身性硬化症（SSC）是一种全身性自身免疫性风湿病，其特征是血管病， 炎症和纤维化，并且具有所有全身自身免疫的情况最高的病例特异性死亡率 风湿病。间质性肺疾病（ILD），这是一组与以下特征的肺部疾病。 肺泡炎症，损伤和纤维化不是由于感染或肿瘤而引起的，影响了40-60％的SSC成年人 这是该人群死亡和住院的主要原因。 SSC-ild的治疗有限， 并且没有研究测试干预措施，以防止SSC-ILD的发展。 Vasculopathy是 SSC及其最早的表现之一。我们假设内皮损伤和微血管损伤 是在SSC-ILD的发病机理中进行批判性煽动事件，因此是潜在的新型治疗目标 为了预防SSC-ILD。该提案的总体目标是阐明 SSC的成年人中的肺和周围微脉动，内皮功能，肺功能和ILD。 我们将对100名具有SSC的成年人进行前瞻性队列研究，其中我们将结合结构， 功能和分子方法，以了解血管室如何有助于 SSC的ILD的发展。在AIM 1中，我们将量化肺微血管灌注血容量 SSC和SSC-ILD并确定其与周围微血管结构和肺功能的关系。目标 2，我们将比较有和没有ILD的SSC患者的外周微血管内皮功能 并确定周围微血管内皮功能与肺部的关系 SSC成年人的微血管灌注，周围微血管结构和肺功能。在AIM 3中，我们 将执行循环内皮细胞的单细胞RNA测序以发现分子机制 这将SSC的成年人与SSC-ILD的成年人区分开来。我们的研究有可能产生范式 转移结果将（1）改变我们概念化假定因果关系的方式 SSC中的微血管疾病和ILD，（2）确定在SSC-ILD临床试验中使用的新型结果指标， （3）使我们能够开发新的治疗方法，以预防SSC-ILD。我们 预计这项研究的结果将告知并适用于其他纤维化肺部疾病，从而 为新颖的治疗方法铺平道路。