Evaluation of the Dynamic Reciprocity Between Cells and the Vessel Matrix in Pulmonary Hypertension

肺动脉高压细胞与血管基质之间的动态互易性评估

• 批准号: 10224333
• 负责人: Rubin M. Tuder
• 金额: $ 43.79万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10224333
• 关键词: Address; Animal Diseases; Animal Model; Blood Vessels; Cattle; Cells; Complement; Complement Activation; Complement Inactivators; Data; Disease model; Elements; Enhancers; Environment; Evaluation; Extracellular Matrix; Fingerprint; Gene Expression; Genetic Transcription; Genomic approach; Genomics; Goals; Heterogeneity; Human; Hypertrophy; Image; Immune; Immunofluorescence Immunologic; Individual; Inflammation; Inflammatory; Intervention; Investigation; Lesion; Link; Lung; Lung diseases; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Profiling; Patients; Phenotype; Plasma; Plasma Proteins; Proteins; Proteome; Proteomics; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Role; SU 5416; Sampling; Serum; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular remodeling; base; cohort; complement system; disease heterogeneity; disorder control; extracellular; hemodynamics; human disease; human tissue; inflammatory marker; inflammatory milieu; lung hypoxia; macrophage; member; mouse model; novel strategies; pre-clinical; primary pulmonary hypertension; pulmonary arterial hypertension; synergism; transcriptome

There is growing evidence of the role of inflammation as a trigger and enhancer of pulmonary vascular remodeling in pulmonary hypertension (PH). This PPG focuses on the role of complement as a trigger of pulmonary vascular disease and PH. The overall guiding concept for Project 3 is the key angle of disease heterogeneity at multiple levels: at the whole diseased human lung level, lesional level in a diseased lung, at the level of similar lesions among IPAH lungs, and animal models of PH. It is the central goal of this Proposal to provide the significance of the mechanistic studies developed in Projects 1,2, and 4. Our central hypothesis is that key molecular fingerprints including RNA expression and cellular combined with extracellular proteomes can be used to define molecularly specific pulmonary vascular lesions in PAH. These profiles will reflect prolonged activation of complement and the subsequent remodeled perivascular environment. We rely on a comprehensive approach based on interrogation of human diseased and control lungs, and plasma of a large cohort of well characterized IPAH patients and controls (Aim 1), robust models of severe PH (Aim 2), and mechanistic investigations in the bovine model of hypoxic PH (Aim 3), using high throughput approaches of genomics, proteomics, and immune localization at the lung tissue level. Specifically, AIM 1 will test the hypothesis that there is evidence of complement activation in IPAH pulmonary vascular lesions, which are related to specific proteomic and genomic fingerprints; AIM 2 will Identify shared molecular signatures established from the human IPAH as compared with the bovine and rat SU5416 models of PH, with a focus on prioritization of therapeutic strategies targeting complement and extracellular matrix remodeling; and, AIM 3 will test the hypothesis that blockade of complement in a large animal model of PH will lead to decreased proinflammatory microenvironment and normalization of the pulmonary vascular proteome. This proposal is highly significant as it addresses the key aspect of molecular heterogeneity among pulmonary vascular lesions and among patients, and animal models; it serves to provide a central translational angle to mechanistic studies in Projects 1,2, and 4 as it seeks to identify complement activation markers in diseased human tissue and robust models of disease. Moreover, it will provide evidence linking complement blockade in reverting a PH proinflammatory phenotype and PH proteome. Project 3 introduces highly novel approaches, including the assessment of the proteome and transcriptome at the lesional level, high throughput immunofluorescence imaging at the tissue level, and novel approaches to block complement.

越来越多的证据表明炎症作为肺血管的触发剂和增强剂的作用 肺动脉高压（PH）的重塑。该 PPG 重点关注补体作为触发因素的作用 肺血管疾病和PH。项目3的总体指导思想是疾病的关键角度 多个水平的异质性：在整个患病人类肺水平、患病肺的病变水平、 IPAH 肺部和 PH 动物模型中相似病变的水平。本提案的中心目标是 提供了项目 1、2 和 4 中开展的机制研究的重要性。 我们的中心假设是关键分子指纹，包括 RNA 表达和细胞组合 细胞外蛋白质组可用于定义分子特异性肺血管病变 多环芳烃。这些概况将反映补体的长期激活和随后的重塑 血管周围环境。我们依靠基于询问人类患病者的综合方法 大量特征明确的 IPAH 患者和对照的肺和对照肺以及血浆（目标 1），稳健 严重PH模型（目标2），以及缺氧PH牛模型的机制研究（目标3），使用 肺组织水平的基因组学、蛋白质组学和免疫定位的高通量方法。 具体来说，AIM 1 将检验以下假设：IPAH 肺部有补体激活的证据。 血管病变，与特定的蛋白质组和基因组指纹相关； AIM 2 将识别共享 与牛和大鼠 SU5416 模型相比，从人类 IPAH 建立的分子特征 PH，重点关注针对补体和细胞外基质的治疗策略的优先顺序 改造；并且，AIM 3 将测试以下假设：在 PH 的大型动物模型中阻断补体将 导致促炎微环境减少和肺血管蛋白质组正常化。 该提案非常重要，因为它解决了肺部分子异质性的关键方面 血管病变以及患者和动物模型之间的病变；它的作用是提供一个中心平移角度 项目 1、2 和 4 中的机制研究旨在识别患病细胞中的补体激活标记 人体组织和强大的疾病模型。此外，它将提供证据将补体阻断与 恢复 PH 促炎表型和 PH 蛋白质组。项目 3 引入了高度新颖的方法， 包括在病变水平评估蛋白质组和转录组，高通量 组织水平的免疫荧光成像，以及阻断补体的新方法。