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是肺血管的触发和增强子的作用 肺动脉高压（pH）中的重塑。该PPG着重于补充的作用 肺血管疾病和pH。项目3的总体指导概念是疾病的关键角度 多个层次的异质性：在整个患病的人类肺部，病变水平，患病的肺部，在 IPAH肺中类似病变的水平和pH的动物模型。这是该提议的核心目标 提供在项目1,2和4中开发的机械研究的重要性。 我们的中心假设是关键的分子指纹包括RNA表达和细胞组合 细胞外蛋白质组织可用于定义分子特异性肺血管病变 pah。这些轮廓将反映补体的延长激活和随后的重塑 血管周环境。我们依靠一种基于对人类患病的讯问的全面方法 和对照肺，以及大量表征伊帕（IPAH）患者和对照组的等离子体（AIM 1），可靠 使用低氧pH的牛模型（AIM 2）的严重pH（AIM 2）模型（AIM 3），使用 在肺组织水平上的基因组学，蛋白质组学和免疫定位的高通量方法。 具体而言，AIM 1将检验以下假设：伊帕肺有补体激活的证据 血管病变，与特定的蛋白质组学和基因组指纹有关； AIM 2将确定共享 与牛和大鼠SU5416模型相比，由人类IPAH建立的分子特征 pH，重点是针对补体和细胞外基质的治疗策略的优先级 重塑；并且，AIM 3将检验以下假设：大型pH动物模型中补体的封锁将会 导致促炎的微环境和肺血管蛋白质组的归一化。 该提议非常重要，因为它涉及肺部分子异质性的关键方面 血管病变以及患者以及动物模型；它提供了与 项目1,2和4的机械研究试图识别患病的补体激活标记 人体组织和鲁棒性疾病模型。此外，它将提供链接补充封锁的证据 恢复pH促炎的表型和pH蛋白质组。项目3介绍了高度新颖的方法， 包括评估蛋白质组和在病变水平上的转录组，高通量 在组织水平上进行免疫荧光成像，以及阻止补体的新方法。