Elafin Therapy for Lung Diseases

Elafin 治疗肺部疾病

基本信息

批准号：
8676920
负责人：
Marlene Rabinovitch
金额：
$ 209.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-17 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676920
关键词：
Alkenes Alveolar Anti-Inflammatory Agents Anti-inflammatory Antibodies Apoptosis Biological Assay Biological Markers Blood Vessels Bronchiolitis Obliterans Cells Clinical Data Clinical Investigator Clinical Trials Commit Complement Complement Factor B Data Databases Distal Dose Elastin Functional disorder Graft Rejection Immunobiology Immunosuppression Injury Instruction Ischemia Lesion Losartan Lung Lung diseases Microcirculation Modeling Mus Natural regeneration Newborn Infant PI3 gene Pathology Patients Physicians Physiological Physiology Program Research Project Grants Property Pulmonary Hypertension Pulmonology Research Research Personnel Rodent Scientist Seasons Serine Signal Transduction Smooth Muscle Myocytes Testing Transforming Growth Factors Translational Research Transplantation Vascular Diseases Ventilator Writing adenoviral-mediated antimicrobial effective therapy elastase inhibitor gene therapy hemodynamics human disease lung development neutrophil elastase inhibitor novel post-doctoral training pre-clinical prevent pulmonary arterial hypertension tool translational medicine vessel regression

项目摘要

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.

描述（由申请人提供）：我们汇集了医学科学家，以追求令人兴奋的临床前数据，这些数据表明内源性中性粒细胞弹性蛋白酶抑制剂 elafin 是一种高效疗法，可治疗三种极具挑战性的肺部疾病：肺动脉高压 (PAH)、呼吸机引起的未成熟肺损伤和肺移植拒绝。项目 I 寻求初步数据支持这一前提，即 elafin 可以逆转 PAH 患者的内皮细胞和平滑肌细胞功能障碍，从而实现远端血管再生和闭塞性病变消退。通过评估elafin是否可以引起啮齿动物病理学的消退，从而更接近地再现人类疾病的血流动力学和结构特征，将扩展先前使用弹性蛋白酶抑制剂逆转实验诱导的PAH的成功。我们还将确定 apelin 是否会增强 elafin 的作用，因为 BMPRII 信号传导功能失调会降低 apelin 水平。项目 II 致力于通过减少 TGFB 激活、肺细胞凋亡和受损的肺泡形成，成功使用 elafin 来保护机械通气的新生小鼠肺部。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 elafin 的作用。项目 III 在令人兴奋的初步数据中表明，elafin 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。该项目进一步研究将弹性蛋白与低剂量免疫抑制剂相结合或通过直接应用于移植物的腺病毒介导的基因治疗实现高水平弹性蛋白的功效。在所有三个项目中，都研究了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对最有可能对弹性蛋白产生反应的患者进行分层的功效。由熟练临床研究人员组成的强大生物标志物核心负责协调生物测定、患者数据库以及肺和血管功能的生理研究。行政核心促进了肺转化医学领域的信息交流和博士后培训，并促进了我们将 elafin 纳入下一个周期临床试验的战略。