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

摘要 这项修订后的R 03奖将评估新的假设，即替代补体途径是一个关键的 结缔组织病相关肺动脉介质和潜在治疗靶点 高血压（CTD-PAH）。这项工作将使本杰明科曼博士，目前NIAMS K 08获奖者， 开发新的研究领域，培养独立性。所描述的研究建立在令人兴奋的 TNF转基因小鼠（TNF-Tg）作为CTD-PAH新模型的初步数据。具体目标1 通过杂交TNF-Tg小鼠评估补体基因消融预防PAH表型的能力 补体成分3（C3）缺陷小鼠。为了确定这种效应对CTD-PAH的特异性， 将观察到的效果与具有由Sugen诱导的肺动脉高压的WT和C3缺陷小鼠进行比较。 缺氧模型具体目标2将进一步探索补体的机制作用，以评估TNF和 肺动脉内皮细胞补体调节粘附分子和凋亡， 这些表型需要经典的或替代的补体因子，并评估内皮细胞 衍生补体可改变巨噬细胞表型。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（旁路途径特异性），以评估 用补体抑制治疗TNF-Tg小鼠是否可以逆转已建立的PAH，以及这是否是 特定于替代途径。该提案将提供关键的初步数据， 科曼博士将研究补体级联在CTD-PAH中的病理作用 和相关的血管病变。

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.