Complement Mediated Remodeling in Pulmonary Vascular Disease

肺血管疾病中补体介导的重塑

• 批准号: 10470731
• 负责人: Kurt R. Stenmark
• 金额: $ 275.42万
• 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/10470731
• 关键词: Address; Age; Animal Model; Animals; Automobile Driving; Biological Markers; Biological Models; Blood Platelets; Blood Vessels; Cattle; Cells; Cessation of life; Chimeric Proteins; Chronic; Clinical; Complement; Complement Activation; Development; Diagnosis; Disease; Disease Progression; Endothelium; Environment; Experimental Animal Model; Extracellular Matrix; Genetic Transcription; Goals; Heterogeneity; Human; Hypoxia; Image; Immunity; Immunoglobulins; Individual; Inflammation; Inflammatory; Intervention; Investigation; Lead; Lesion; Link; Lung; Mass Spectrum Analysis; Mediating; Methodology; Modeling; Molecular; Molecular Profiling; Monoclonal Antibodies; Morbidity - disease rate; Mouse Protein; Mus; Natural Immunity; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Platelet Activation; Play; Positioning Attribute; Process; Proteome; Proteomics; Pulmonary Hypertension; Pulmonary arterial remodeling; Rattus; Research Personnel; Resolution; Role; SU 5416; Schistosoma; Schistosomiasis; Shapes; Signal Transduction; Site; T-Lymphocyte; Techniques; Testing; Thrombospondin 1; Tissues; Transplantation; United States Food and Drug Administration; Vascular remodeling; adaptive immunity; antibody detection; circulating biomarkers; complement pathway; disease heterogeneity; extracellular; hypoxia-induced pulmonary hypertension; in vivo; individualized medicine; inhibitor; lung vascular inflammation; macrophage; monocyte; mortality; neoantigens; novel; novel therapeutics; pulmonary arterial hypertension; pulmonary vascular disorder; recruit; sex; translational goal; treatment response

Pulmonary arterial hypertension (PAH) afflicts patients of both sexes and across a broad age range and is highly lethal, if not promptly diagnosed and appropriately treated. Despite advances in the understanding of its pathogenesis and the development of 14 therapies approved by the United States Food and Drug Administration (FDA) over the past 2-3 decades, it continues to be associated with significant morbidity and mortality. The fundamental premise in this PPG is that PAH is highly heterogeneous regarding clinical parameters including initiating factors, clinical presentation, rate of progression, and response to therapy. Importantly, patient-to- patient heterogeneity, involving the types of pulmonary vascular lesions and the corresponding endotypes (i.e., underlying molecular processes driving the specific disease presentation), has been uncovered by our group and underlies the high complexity of disease pathogenesis. The paucity of investigations of these broader aspects of heterogeneity has resulted in a lack of understanding of specific factors contributing to particular sub- phenotypes of PAH – negatively impacting the development of more targeted (and individualized) therapies. These limitations manifest in the fact that some patients live many years on currently available treatments – however without cure of their disease -, while others progress rapidly and inexorably from onset to transplantation or death. This proposal seeks to uncover novel pathogenetic processes linking pulmonary vascular inflammation, remodeling, and molecular underpinnings of pulmonary vascular lesions in PH, while recognizing the key pathological and pathobiological heterogeneity of the disease. The central premise to be tested in this proposal is that early and persistent local, pulmonary vascular-specific activation of complement leads to persistent perivascular inflammation and extracellular matrix changes, thus shaping a feed-forward loop of pro- inflammatory/pro-remodeling perivascular microenvironment, leading to development of PH. This application represents a major step towards identifying new biomarkers and more effective individualized treatments, which are critically needed.

肺动脉高压 (PAH) 困扰着不同性别和各个年龄段的患者，并且发病率很高。 如果不及时诊断和适当治疗，将致命。尽管人们对它的认识不断进步 发病机制以及美国食品和药物管理局批准的 14 种疗法的开发 (FDA) 在过去的 2-3 年里，它仍然与显着的发病率和死亡率相关。这 该 PPG 的基本前提是 PAH 在临床参数方面具有高度异质性，包括 起始因素、临床表现、进展率和治疗反应。重要的是，患者对 患者异质性，涉及肺血管病变的类型和相应的内型（即， 我们的团队已经发现了驱动特定疾病表现的潜在分子过程 并且是疾病发病机制高度复杂性的基础。缺乏对这些更广泛领域的调查 异质性的各个方面导致了对导致特定亚组的具体因素缺乏了解 PAH 表型——对更有针对性（和个体化）疗法的开发产生负面影响。 这些局限性体现在一些患者依靠目前可用的治疗可以活很多年的事实 - 然而，他们的疾病无法治愈，而其他人从发病到移植的进展迅速且不可阻挡 或死亡。该提案旨在揭示与肺血管炎症相关的新发病过程， PH 中肺血管病变的重塑和分子基础，同时认识到关键 该疾病的病理学和病理生物学异质性。本节要测试的中心前提 提议是，补体引线的早期和持续的局部肺血管特异性激活 持续的血管周围炎症和细胞外基质变化，从而形成前馈 促炎症/促重塑血管周围微环境的循环，导致 PH值。该应用代表了朝着识别新生物标记物和更有效的方向迈出的重要一步 个体化治疗，这是迫切需要的。