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

摘要 这项修订的R03奖将评估替代补体途径是关键的这一新假设 结缔组织病相关肺动脉的介体和潜在治疗靶点 高血压(CTD-PAH)。这项工作将使现任NIAMS K08奖获得者本杰明·科曼博士能够 开拓新的研究领域，自主发展。所描述的研究建立在令人兴奋的基础上 肿瘤坏死因子转基因小鼠作为CTD-PAH新模型的初步研究具体目标1 通过与肿瘤坏死因子-甘油三酯小鼠杂交，评估补体基因消融预防PAH表型的能力 补体成分3(C3)缺乏的小鼠。为了确定这种效应对CTD-PAH的特异性， 所看到的效果将与WT和C3缺乏的小鼠进行比较，这些小鼠由SUGEN-1诱导的肺动脉高压。 缺氧模型。具体目标2将进一步探讨补体的机械作用，以评估肿瘤坏死因子和 补体在肺动脉内皮细胞中调节黏附分子和细胞凋亡 这些表型需要经典的或替代的补充因子，并评估内皮细胞如何 衍生补体可能改变巨噬细胞的表型。在具体目标3中，我们将使用融合蛋白 补体抑制剂CR2-CRY(PAN-补体)和CR2-FH(替代途径特异性)评估 用补体抑制治疗肿瘤坏死因子-甘油三酯小鼠是否能逆转已建立的PAH 特定于另一条路径。该提案将提供关键的初步数据，这些数据将构成 在R01奖中，Korman博士将研究补体级联在CTD-PAH中的病理作用 和相关的血管病变使用患者材料和动物模型。

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.