Elafin Therapy for Lung Diseases

Elafin 治疗肺部疾病

• 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
• 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

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)： 我们聚集了内科科学家，寻求令人振奋的临床前数据，表明内源性中性粒细胞弹性蛋白酶抑制剂elafin是治疗三种非常具有挑战性的肺部疾病的高效药物，这三种疾病分别是肺动脉高压(PAH)、呼吸机诱导的未成熟肺损伤和肺移植排斥反应。项目I追求的初步数据支持这一前提，即Elafin可以逆转PAH患者的内皮和平滑肌细胞功能障碍，从而允许远端血管再生和闭塞性病变的消退。之前成功使用弹性酶抑制剂逆转实验诱导的PAH，将通过评估Elafin是否可以导致更紧密地再现人类疾病的血流动力学和结构特征的啮齿动物病理的退化来扩展。我们还将确定apelin是否会增强elafin的作用，因为功能失调的BMPRII信号会降低apelin的水平。项目II旨在通过减少TGFb激活、肺细胞凋亡和受损的肺泡形成，成功地使用Elafin来保护机械通气的新生小鼠肺。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，弹力芬可以保护小鼠气管移植模型的微循环，并防止与毛细支气管炎闭塞性肺炎相关的呼吸道缺血。该项目进一步研究了将弹力素与低剂量免疫抑制药物相结合或通过腺病毒介导的基因治疗直接应用于移植获得高水平弹力素的有效性。在所有三个项目中，都研究了弹性蛋白降解的生物标记物，以此作为判断弹性蛋白反应的工具。我们将研究这些生物标记物在对最有可能对Elafin有反应的患者分层中的有效性。由熟练的临床研究人员组成的强大的Biomarker核心协调了生物检测、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方面的信息交换和博士后培训，并促进了我们在下一个周期将Elafin投入临床试验的战略。