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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要系统性硬化症（SSc）是一种系统性自身免疫性风湿性疾病，其特征是血管病变，炎症和纤维化，并且在所有系统性自身免疫性疾病中具有最高的病例特异性死亡率风湿性疾病。间质性肺病（ILD）是一组密切相关的肺部疾病，其特征是非感染或肿瘤所致的肺泡炎症、损伤和纤维化影响 40-60% 的 SSc 成人是该人群死亡和住院的主要原因。 SSc-ILD 的治疗方法有限，目前还没有研究测试过预防 SSc-ILD 发展的干预措施。血管病变的一个标志是 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 SSc-ILD 发病机制中的关键诱发事件，因此是潜在的新治疗靶点用于预防 SSc-ILD。该提案的总体目标是阐明之间的关系成年 SSc 患者的肺和外周微血管、内皮功能、肺功能和 ILD。我们将对 100 名患有 SSc 的成年人进行一项前瞻性队列研究，其中我们将结合结构、功能和分子方法来了解血管室如何促进 SSc 中 ILD 的发展。在目标 1 中，我们将量化肺微血管灌注血量 SSc和SSc-ILD并确定其与外周微血管结构和肺功能的关系。瞄准 2、我们将比较伴有和不伴有ILD的SSc患者的外周微血管内皮功能并确定外周微血管内皮功能与肺功能的关系成人 SSc 的微血管灌注、外周微血管结构和肺功能。在目标 3 中，我们将对循环内皮细胞进行单细胞 RNA 测序，以揭示分子机制区分患有 SSc 的成人和患有 SSc-ILD 的成人。我们的研究有可能产生范式—— 改变结果将（1）改变我们概念化之间假定的因果关系的方式 SSc 中的微血管疾病和 ILD，(2) 确定用于 SSc-ILD 临床试验的新结果指标， (3) 使我们能够开发用于 SSc-ILD 一级和二级预防的新疗法。我们预计这项研究的结果将指导并适用于其他纤维化肺疾病，从而为新的治疗方法铺平道路。