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）困扰着两种性别和广泛年龄范围的患者，并且高度相关。 致命的，如果不及时诊断和适当治疗。尽管在理解其 发病机制和美国食品和药物管理局批准的14种治疗方法的发展 (FDA)在过去的二、三十年里，它仍然与高发病率和死亡率有关。的 本PPG的基本前提是PAH在临床参数方面具有高度异质性，包括 启动因素、临床表现、进展速度和对治疗的反应。重要的是，患者对 患者异质性，包括肺血管病变的类型和相应的内型（即， 驱动特定疾病表现的潜在分子过程），已经被我们的小组发现 并揭示了疾病发病机制的高度复杂性。对这些更广泛的问题缺乏调查， 异质性方面导致缺乏对特定子系统的具体因素的理解， PAH的表型-对更有针对性（和个性化）治疗的开发产生负面影响。 这些局限性表现在这样一个事实上，即一些患者在目前可用的治疗中存活多年- 而另一些人则从发病到移植迅速而无情地进展 或者死亡该提案旨在揭示与肺血管炎症相关的新的发病过程， 重塑，以及PH中肺血管病变的分子基础，同时认识到 疾病的病理学和病理生物学异质性。在这方面要检验的中心前提是， 建议是早期和持续的局部、肺血管特异性补体激活导致 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环，导致 博士这一应用代表了朝着确定新的生物标志物和更有效的方法迈出的重要一步。 个性化治疗，这是非常必要的。