DYSREGULATED ANGIOGENESIS IN SCLERODERMA-ASSOCIATED PAH

这项建议将调查自身免疫和系统性肺血管疾病之间的联系。 硬化症(硬皮病)。我们将使用一大批具有良好特征的硬皮病患者 在约翰·霍普金斯硬皮病中心被前瞻性地跟踪，询问如何 可能会发生免疫介导的血管损伤，如果这种损伤导致肺动脉高压。 我们发现，颗粒酶B(GRB)是一种从细胞毒淋巴细胞中释放出来的蛋白酶，可以裂解 纤溶酶原和纤维蛋白-1，已知对血管的完整性很重要的蛋白质。我们的数据 提示纤溶酶原的GRB裂解释放了血管抑素，这是我们发现的一种血管抑制分子 我们的硬皮病患者的血浆中增加了。我们有更多的证据表明 已知的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受损的病理过程是直接的 与自身免疫介导的炎症过程有关；这一过程可以在小范围内测量 患者的实时出血量；GRB裂解释放的产品将反映这种疾病 在临床表现明显之前的过程，因此血浆血管抑素和/或异常水平 裂解纤维蛋白-1片段将预测肺动脉高压的临床重要转归 硬皮病的其他血管疾病。这个项目的总体假设是，失调的 血管生成发生在硬皮病相关性肺动脉高压中，并被介导和传播 通过颗粒酶B途径的细胞自身免疫过程。特定目标#1将调查特定目标 血管生成调节因子可能是高血压发生发展的生物标志物 前瞻性地跟踪了具有良好特征的硬皮病患者队列，通过定义临床 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 测量并将这一结果与潜在的感兴趣的生物标记物进行关联。具体目标#2将 明确GRB在硬皮病肺动脉高压患者血管抑素生成中的作用。 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裂解的纤维蛋白-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.