Elafin Therapy for Lung Diseases

描述（由申请人提供）： 我们将医生科学家聚集在一起，追求令人兴奋的临床前数据，表明内源性中性粒细胞弹性蛋白酶抑制剂elafin是三种非常具有挑战性的肺部疾病，肺动脉高压（PAH），呼吸机诱导的未成熟肺损伤和肺移植排斥反应的高效疗法。项目I寻求支持以下前提的初步数据：弹性蛋白酶可以逆转PAH患者的内皮和平滑肌细胞功能障碍，使远端血管再生和闭塞性病变消退。先前成功使用弹性蛋白酶抑制剂逆转实验诱导的PAH将通过评估弹性蛋白酶是否可以引起啮齿动物病理学的消退来扩展，该啮齿动物病理学更接近地再现了人类疾病的血流动力学和结构特征。我们还将确定弹性蛋白酶的作用是否会被爱帕琳增强，因为爱帕琳水平会因BMPRII信号传导功能障碍而降低。项目II追求成功使用弹力素保护机械通气的新生小鼠肺，通过减少TGFB激活，肺细胞凋亡和受损的肺泡形成。项目II确定是否可以通过使用抗体或氯沙坦直接阻断增强的TGFIS活性来增强弹力素的作用。项目III显示，在令人兴奋的初步数据中，弹力素可以保护小鼠气管移植模型中的微循环，并预防与闭塞性细支气管炎相关的气道缺血。该项目进一步研究了将elafin与低剂量免疫抑制相结合或通过直接应用于移植的腺病毒介导的基因治疗实现高水平elafin的功效。在所有三个项目中，研究弹性蛋白降解的生物标志物作为判断弹性蛋白反应性的工具。我们将研究这些生物标志物在对最有可能对弹性蛋白酶有反应的患者进行分层中的疗效。由熟练临床研究人员组成的强大生物标志物核心协调生物测定、患者数据库以及肺和血管功能的生理学研究。行政核心促进了肺部转化医学的信息交流和博士后培训，并促进了我们在下一个周期将elafin推向临床试验的战略。

DESCRIPTION (provided by applicant): We bring together physician scientists to pursue exciting pre-clinical data indicating that the endogenous neutrophil elastase inhibitor, elafin, is a highly effective therapy for three very challenging lung conditions, pulmonary hypertension (PAH), ventilator induced injury of the immature lung and lung transplant rejection. Project I pursues preliminary data supporting the premise that elafin can reverse the endothelial and smooth muscle cell dysfunction in patients with PAH, to allow regeneration of distal blood vessels and regression of obliterative lesions. The previous successful use of elastase inhibitors to reverse experimentally-induced PAH will be extended by assessing whether elafin can cause regression of a rodent pathology that more closely reproduces the hemodynamic and structural features of human disease. We will also determine whether the action of elafin will be enhanced by apelin, since apelin levels are reduced by dysfunctional BMPRII signaling. Project II pursues the successful use of elafin in protecting the mechanically ventilated newborn mouse lung, by reducing TGFB activation, lung cell apoptosis and impaired alveolar formation. Project II determines whether the action of elafin can be enhanced by direct blockade of enhanced TGFIS activity using an antibody or losartan. Project III shows, in exciting preliminary data, that elafin can protect the microcirculation in the murine tracheal transplant model, and prevent airway ischemia associated with bronchiolitis obliterans. This project further investigates the efficacy of combining elafin with low dose immunosuppression or of achieving high levels of elafin by adenoviral mediated gene therapy applied directly to the transplant. In all three projects, biomarkers of elastin degradation are investigated as a tool to judge elafin responsiveness. We will investigate the efficacy of these biomarkers in stratifying patients most likely to respond to elafin. A strong Biomarker Core of skilled clinical investigators coordinates the bioassays, the patient database and the physiological studies of lung and vascular function. The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle.