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）：