Complement Mediated Remodeling in Pulmonary Vascular Disease

肺血管疾病中补体介导的重塑

• 批准号: 10024460
• 负责人: Kurt R. Stenmark
• 金额: $ 279.1万
• 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/10024460
• 关键词: Address; Age; Animal Model; Animals; Antibodies; Automobile Driving; Biological Markers; Biological Models; Blood Platelets; Blood Vessels; Cattle; Cells; Cessation of life; Chimeric Proteins; Chronic; Clinical; Complement; Complement Activation; Detection; 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 artery structure; 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 Diseases; Vascular remodeling; adaptive immunity; base; circulating biomarkers; complement pathway; disease heterogeneity; extracellular; in vivo; individualized medicine; inhibitor/antagonist; macrophage; monocyte; mortality; neoantigens; novel; novel therapeutics; pulmonary arterial hypertension; recruit; response; sex; vascular inflammation

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）困扰着男女的患者，并且在广泛的年龄范围内 致命，即使没有及时诊断和适当治疗。尽管在理解它的理解方面取得了进步 美国食品药品监督管理局批准的14种疗法的发病机理和开发 （FDA）在过去的2-3年中，它继续与显着的发病率和死亡率有关。 该PPG的基本前提是PAH在包括 引发因素，临床表现，进展率和对治疗的反应。重要的是，患者到患者 患者异质性，涉及肺血管病变的类型和相应的内型（即 我们的小组发现了驱动特定疾病表现的基本分子过程） 并构成了疾病发病机理的高复杂性。对这些更广泛的调查很少 异质性方面的各个方面导致对有助于特定子的特定因素缺乏了解 PAH的表型 - 对更有针对性（和个性化）疗法的发展产生负面影响。 这些局限性在以下事实中表明，某些患者在目前可用的治疗中生活了很多年 - 但是，没有治愈疾病的治愈，而其他人则从发作到移植迅速而无情地进展 或死亡。该建议旨在发现与肺血管感染联系在一起的新型致病过程， pH中的肺血管病变的重塑和分子基础，同时识别钥匙 在此要测试的中央前提 提案是，早期和持续的局部，肺血管特异性激活的完成铅 持续的血管周围注射和细胞外基质变化，从而形成前馈 促炎/促疾病的循环循环，导致发展 ph。该应用程序代表了识别新生物标志物和更有效的主要步骤 迫切需要的个性化治疗方法。