DYSREGULATED ANGIOGENESIS IN SCLERODERMA-ASSOCIATED PAH

该提案将调查系统性自身免疫与肺血管疾病之间的联系 硬化症（硬皮病）。我们将使用大量特征明确的硬皮病患者群体，他们将 在约翰霍普金斯大学硬皮病中心进行前瞻性跟踪，以询问如何 可能会发生免疫介导的脉管系统损伤，并且这种损伤会导致肺动脉高压。 我们发现颗粒酶 B (GrB) 是一种从细胞毒性淋巴细胞释放的蛋白酶，可以裂解 纤溶酶原和原纤维蛋白-1 是已知对血管完整性很重要的蛋白质。我们的数据 表明 GrB 裂解纤溶酶原释放血管抑制素，这是我们发现的一种血管抑制分子 我们的硬皮病患者血浆中增加。我们有更多证据表明不平衡 已知调节血管重塑和血管生成的循环血管生成因子。我们 怀疑硬皮病患者肺部血管损伤的病理过程直接与 与自身免疫介导的炎症过程有关；这个过程可以在很小的范围内进行测量 患者的实时血量； GrB 裂解释放的产物将反映这种疾病 在临床明显出现血管抑制素和/或血管抑制素血浆水平异常之前的过程 裂解的 fibrillin-1 片段将预测肺动脉高压的临床重要结果和 硬皮病中的其他血管疾病。该项目的总体假设是，失调 血管生成发生在硬皮病相关的肺动脉高压中并被介导和传播 通过颗粒酶 B 途径的细胞自身免疫过程。具体目标 #1 将调查具体 血管生成调节因子作为肺动脉高压发展的可能生物标志物 通过定义临床特征，对具有良好特征的硬皮病患者进行前瞻性随访 使用预先设计的最先进的临床和实验室结果新的肺动脉高压 测量并将该结果与潜在的感兴趣的生物标志物相关联。具体目标 #2 将 定义 GrB 在硬皮病肺动脉高压患者产生血管抑制素中的作用。 具体目标 #3 将确定是否可以在循环中的硬皮病中检测到 GrB 裂解的 fibrillin-1 或相关组织。

This proposal will investigate the link between autoimmunity and pulmonary vascular disease in systemic sclerosis (scleroderma). We will use a large well-characterized population of scleroderma patients who will be followed prospectively at the Johns Hopkins Scleroderma Center to interrogate the question of how immune-mediated injury to the vasculature can occur and if this injury leads to pulmonary hypertension. We have discovered that Granzyme B (GrB), a protease released from cytotoxic lymphocytes, can cleave plasminogen and fibrillin-1, proteins known to be important to the integrity of the blood vessels. Our data suggest that GrB cleavage of plasminogen releases angiostatin, an angiostatic molecule that we find increased in the plasma our patients with scleroderma. We have additional evidence of an imbalance of circulating angiogentic factors that are known to regulate vascular remodeling and angiogenesis. We suspect that the pathological process damaging vessels in the lung of scleroderma patients is directly linked to an autoimmune mediated inflammatory process; that this process can be measured in the small volumes of blood from patients in real time; that products released by GrB cleavage will reflect this disease process before it is clinically apparent and therefore abnormal plasma levels of angiostatin and/or fragments of cleaved fibrillin-1 will predict the clinically important outcome of pulmonary hypertension and other vascular disease in scleroderma. The overall hypothesis in this project is that dysregulated angiogenesis occurs in scleroderma-associated pulmonary hypertension and is mediated and propagated by a cellular autoimmune process via the Granzyme B pathway. Specific Aim #1 will investigate specific regulators of angiogenesis as possible biomarkers for the development of pulmonary hypertension in a prospectively followed cohort of well-characterized patients with scleroderma by defining the clinical outcome new pulmonary hypertension using a pre-designed state-of-the-art clinical and laboratory measurements and correlating this outcome with the potential biomarkers of interest. Specific Aim #2 will define the role of GrB in generating angiostatin in patients with scleroderma pulmonary hypertension. Specific Aim #3 will define whether GrB cleaved fibrillin-1 can be detected in scleroderma in the circulation or relevant tissues.