Targeting Pulmonary Hypertension with R-Ras

描述（由申请人提供）：血液通常以相对较低的压力通过肺部循环。在肺动脉高压（PAH）中，这种压力增加，通常原因不明。最近的研究结果表明，PAH的根本问题可能是肺动脉壁的肌肉层增厚。与此同时，形成血管内层的细胞，即内皮细胞，通过获得正常血管内皮细胞上不存在的细胞表面蛋白而发生变化。我们最近发现，一种称为R-Ras的细胞内蛋白可以抵消PAH中发生的血管变化类型。我们建议将R-Ras开发为PAH的新治疗方法。为了增强R-Ras蛋白向患病肺血管的递送，我们将在R-Ras蛋白上附加肽信号，该肽信号将选择性地将其递送至肺血管。一旦R-Ras到达患病血管，另一种肽信号将其转运到血管壁细胞内，在那里它将起作用以防止被认为是PAH根本原因的变化。我们将首先测试几种候选肽在大鼠模型中靶向PAH的能力。选择的肽将与R-Ras缀合以产生PAH靶向功能蛋白。然后，我们将测试它们在细胞培养中的作用，并选择最有前途的化合物。我们希望在第一阶段的赠款，我们可以靶向R-Ras病变血管，它是活跃的。这一可行性证明将为R-Ras进一步开发为PAH的新型治疗方法奠定基础。公共卫生相关性：肺动脉高压（PAH）是一种原发性和继发性疾病，影响数十万美国人。这种疾病是渐进的和严重的：它可能导致心脏右侧的衰竭，这一侧通过肺部处理血液循环。目前的治疗只能缓解症状; 50%的PAH患者在5年内死于该病。我们建议开发的新疗法将攻击PAH的根本原因，也可能解决具有类似特征的其他血管疾病。

DESCRIPTION (provided by applicant): Blood normally circulates through the lungs at a relatively low pressure. In pulmonary arterial hypertension (PAH) this pressure is increased, often for unknown reasons. Recent results suggest that the underlying problem in PAH may be the thickening of the muscular layer in the walls of lung arteries. At the same time, the cells that form the inner lining of blood vessels, endothelial cells, change by acquiring cell surface proteins that are not present on endothelial cells of normal vessels. We recently made the discovery that an intracellular protein known as R-Ras can counteract the types of blood vessel changes that occur in PAH. We propose to develop R-Ras into a new treatment for PAH. To enhance the delivery of the R-Ras protein to the diseased lung vasculature, we will attach a peptide signal to the R-Ras protein that will selectively deliver it to lung vessels. Once R-Ras has reached the diseased vessels, another peptide signal transports it inside the cells in the vessel wall, where it will act to prevent the changes that are believed to be the root cause of PAH. We will first test several candidate peptides for their ability to target PAH in a rat model. The selected peptides will be conjugated to R-Ras to produce PAH-targeted functional proteins. We will then test them for their effects in cell culture and select the most promising compounds. We hope to show during Phase I of the grant that we can target R-Ras to the diseased vessels and that it is active. This demonstration of feasibility would form the basis of further development of R-Ras into a novel therapy for PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a disease that in its primary and secondary forms affects hundreds of thousands of Americans. The disease is progressive and serious: it can lead to the failure of the right side of the heart, the side that handles blood circulation through the lungs. The current treatments can only relieve the symptoms; 50 % of PAH patients succumb to the disease within 5 years. The new therapy we propose to develop will attack an underlying cause of PAH and may also address other vascular diseases with similar features.