DYSREGULATED ANGIOGENESIS IN SCLERODERMA-ASSOCIATED PAH

本研究将探讨自身免疫与肺血管疾病之间的联系， 硬皮病（scleroderma）我们将使用大量特征明确的硬皮病患者， 在约翰霍普金斯硬皮病中心进行前瞻性随访，询问如何 可能发生免疫介导的脉管系统损伤，并且如果这种损伤导致肺动脉高压。 我们已经发现颗粒酶B（GrB），一种从细胞毒性淋巴细胞释放的蛋白酶，可以切割 纤溶酶原和纤溶酶-1，已知对血管完整性重要的蛋白质。我们的数据 表明GrB裂解纤溶酶原释放血管抑素，我们发现血管抑制分子， 在硬皮病患者的血浆中增加。我们有额外的证据表明 已知循环的血管生成因子调节血管重塑和血管生成。我们 我们怀疑硬皮病患者肺血管损害的病理过程是直接的， 与自身免疫介导的炎症过程有关;这一过程可以在小的 真实的时间内患者的血液体积; GrB裂解释放的产物将反映这种疾病 在临床上明显之前进行，因此血浆血管抑素水平异常和/或 切割的β-淀粉样蛋白-1的片段将预测肺动脉高压的临床重要结果， 硬皮病中的其他血管疾病。这个项目的总体假设是， 硬皮病相关肺动脉高压中发生血管生成，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生的可能生物标志物， 前瞻性随访了一组特征明确的硬皮病患者， 使用预先设计的最先进的临床和实验室结果新发肺动脉高压 测量并将该结果与感兴趣的潜在生物标志物相关联。具体目标#2 明确GrB在硬皮病肺动脉高压患者中产生血管抑素的作用。 具体目标#3将定义GrB切割的Risin-1是否可以在循环中的硬皮病中检测到 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.