Role of the Alternative Complement Cascade in Connective Tissue Disease Associated Pulmonary Arterial Hypertension (CTD-PAH)

替代补体级联在结缔组织病相关肺动脉高压 (CTD-PAH) 中的作用

基本信息

批准号：
10250498
负责人：
Benjamin Douglas Korman
金额：
$ 7.47万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250498
关键词：
Ablation Affect Alternative Complement Pathway Animal Model Animals Apoptosis Area Award Biological Blood Vessels Cause of Death Cell Adhesion Molecules Cessation of life Chimeric Proteins Complement Complement 3 Complement 3d Receptors Complement Activation Complement Factor D Complement Inactivators Connective Tissue Diseases Data Deposition Endothelial Cells Endothelium Etiology FDA approved Foundations Future Genetic Genomics Human Hypoxia Immunohistochemistry Lead Lesion Literature Lung Mediating Mediator of activation protein Modeling Morbidity - disease rate Mus National Institute of Arthritis and Musculoskeletal and Skin Diseases Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Placebos Pulmonary Hypertension Pulmonary vessels Research Role Serum Signal Pathway Specificity Study of serum System Systemic Scleroderma TNF gene Testing Transgenic Mice Transgenic Organisms Treprostinil Vascular Diseases Vasodilator Agents Work base complement pathway effective therapy experimental study inhibitor/antagonist macrophage mortality mortality risk mouse model novel patient subsets prevent pulmonary arterial hypertension pulmonary artery endothelial cell pulmonary function targeted treatment therapeutic target transcriptome sequencing

项目摘要

Abstract This revised R03 award will assess the novel hypothesis that the alternative complement pathway is a critical mediator and potential therapeutic target for connective tissue disease associated pulmonary arterial hypertension (CTD-PAH). This work will allow Dr. Benjamin Korman, a current NIAMS K08 awardee, to develop a new area of research and develop independence. The studies described build upon exciting preliminary data characterizing TNF transgenic mice (TNF-Tg) as a novel model of CTD-PAH. Specific aim 1 assesses the ability of genetic ablation of complement to prevent the PAH phenotype by crossing TNF-Tg mice with complement component 3 (C3) deficient mice. To determine the specificity of this effect to CTD-PAH, the effect seen will be compared to WT and C3 deficient mice with pulmonary hypertension induced by the Sugen- hypoxia model. Specific aim 2 will further explore complement’s mechanistic role to assess how TNF and complement in pulmonary artery endothelial cells regulate adhesion molecules and apoptosis, whether classical or alternative complement factors are required for these phenotypes, and assess how endothelial cell derived complement may alter macrophage phenotypes. In specific aim 3, we will use fusion-protein complement inhibitors CR2-Crry (pan-complement) and CR2-fH (alternative pathway specific) to assess whether treatment of TNF-Tg mice with complement inhibition can reverse established PAH and whether this is specific to the alternative pathway. This proposal will provide critical preliminary data which will form the basis for an R01 award in which Dr. Korman will study the pathological role of the complement cascade in CTD-PAH and associated vasculopathy using patient materials and animal models.

抽象的这项修订后的R03奖将评估替代完成途径是关键的新颖假设结缔组织疾病相关肺动脉的介体和潜在的治疗靶标高血压（CTD-PAH）。这项工作将使现任Niams K08获奖者本杰明·科尔曼（Benjamin Korman）发展一个新的研究领域并发展独立性。研究描述的是基于令人兴奋的将TNF转基因小鼠（TNF-TG）表征为CTD-PAH的新模型的初步数据。具体目标1 评估通过跨越TNF-TG小鼠的遗传灌溉完成以防止PAH表型的能力完成组件3（C3）缺乏小鼠。为了确定这种影响对CTD-PAH的特异性，看到的效应将与sugen-诱导的肺动脉高压的WT和C3缺乏小鼠进行比较缺氧模型。具体目标2将进一步探讨完成的机械作用，以评估TNF和补充肺动脉内皮细胞调节粘附分子和凋亡，是否是否存在这些表型需要经典或替代补体因素，并评估内皮细胞如何得出的完成可能会改变巨噬细胞表型。在特定目标3中，我们将使用融合蛋白补体抑制剂CR2-Crry（PAN-COMPLENT）和CR2-FH（特定于替代途径）以评估通过完成抑制的TNF-TG小鼠的治疗是否可以逆转确定的PAH以及这是否是特定于替代途径。该建议将提供关键的初步数据，这将构成基础对于R01奖，Korman博士将研究CTD-PAH完成级联的病理作用以及使用患者材料和动物模型的相关血管病。