Targeting Pulmonary Hypertension with R-Ras

描述（由申请人提供）：血液在相对较低的压力下正常地通过肺部循环。肺动脉高压（PAH）患者血压升高，原因不明。最近的研究结果表明，多环芳烃的潜在问题可能是肺动脉壁肌肉层的增厚。同时，形成血管内层的细胞，即内皮细胞，通过获取正常血管内皮细胞所不存在的细胞表面蛋白质而发生变化。我们最近发现一种叫做R-Ras的细胞内蛋白可以抵消多环芳烃引起的血管变化。我们建议开发R-Ras作为治疗多环芳烃的新方法。为了增强R-Ras蛋白向病变肺血管的传递，我们将在R-Ras蛋白上附加一个肽信号，选择性地将其传递到肺血管。一旦R-Ras到达病变血管，另一种肽信号将其运送到血管壁的细胞内，在那里它将起作用，防止被认为是PAH的根本原因的变化。我们将首先在大鼠模型中测试几种候选肽靶向多环芳烃的能力。选择的肽将与R-Ras偶联以产生针对多环芳烃的功能蛋白。然后，我们将在细胞培养中测试它们的效果，并选择最有希望的化合物。我们希望在第一阶段的拨款中证明我们可以将R-Ras靶向病变血管，并且它是活跃的。这一可行性的证明将为进一步发展R-Ras成为治疗多环芳烃的新疗法奠定基础。公共卫生相关性：肺动脉高压（PAH）是一种影响数十万美国人的原发性和继发性疾病。这种疾病是一种进行性且严重的疾病：它会导致负责肺部血液循环的右侧心脏衰竭。目前的治疗只能缓解症状；50%的多环芳烃患者在5年内死于该病。我们建议开发的新疗法将攻击PAH的潜在原因，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.