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.

抽象的修订后的 R03 奖项将评估替代补体途径是关键的新假设结缔组织病相关肺动脉的介质和潜在治疗靶点高血压 (CTD-PAH) 这项工作将使现任 NIAMS K08 获奖者 Benjamin Korman 博士能够开发一个新的研究领域并培养独立性。所描述的研究建立在令人兴奋的基础上。初步数据描述 TNF 转基因小鼠 (TNF-Tg) 作为 CTD-PAH 的新模型。具体目标 1。通过与 TNF-Tg 小鼠杂交来评估补体基因消除预防 PAH 表型的能力为了确定这种效应对 CTD-PAH 的特异性，将观察到的效果与 Sugen-诱导的肺动脉高压的 WT 和 C3 缺陷小鼠进行比较具体目标 2 将进一步探讨补体的机制作用，以评估 TNF 和在肺动脉内皮细胞中调节粘附分子和凋亡补体，是否这些表型需要经典或替代补体因子，并评估内皮细胞如何衍生补体可能会改变巨噬细胞表型。在具体目标 3 中，我们将使用融合蛋白。补体抑制剂 CR2-Crry（泛补体）和 CR2-fH（替代途径特异性）来评估用补体抑制治疗 TNF-Tg 小鼠是否可以逆转已形成的 PAH，这是否是该提案将提供关键的初步数据，作为替代途径的基础。获得 R01 奖，Korman 博士将研究补体级联在 CTD-PAH 中的病理作用使用患者材料和动物模型研究相关血管病变。