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TGFB and Nitric Oxide Signaling in Pediatric Pulmonary Vascular Disease

小儿肺血管疾病中的 TGFB 和一氧化氮信号传导

基本信息

批准号：
9127330
负责人：
JESSE D ROBERTS
金额：
$ 43.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127330
关键词：
Address Adult Agonist Alveolar Animal Model Antibodies Biological Assay Biological Models Blood Vessels Breathing Cell Differentiation process Cells Cessation of life Childhood Clinical Trials Complication Custom Cyclic GMP Development Disease Disease model Down-Regulation Dyspnea Electrophoretic Mobility Shift Assay Evolution Exhibits Fibroblasts Figs - dietary Gene Expression Health Heart failure Hyperplasia Injury Knockout Mice Lead Ligation Lung Lung diseases Mediating Methods Modeling Mus Myofibroblast Newborn Animals Newborn Infant Nitric Oxide Pathway interactions Patients Peripheral Pharmaceutical Preparations Phenotype Plant Roots Play Protein Isoforms Pulmonary Hypertension Pulmonary artery structure RNA Interference Regulation Reporter Research Residual state Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Soluble Guanylate Cyclase Syncope System TGFB1 gene Techniques Testing Therapeutic Time Transforming Growth Factor beta Receptors Transforming Growth Factors Translations Vascular Diseases Vasodilator Agents Work base cell dedifferentiation clinically relevant constriction disability disease phenotype effective therapy improved in vivo inhibitor/antagonist injured lung development lung injury neutralizing antibody new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics prevent promoter pup safety testing small molecule

项目摘要

DESCRIPTION (provided by applicant): Our research focus is to identify and test novel mechanisms that disrupt vascular cGMP signaling in order to develop new therapies that protect pulmonary development in the injured newborn lung. Pediatric pulmonary vascular disease (PVD) causes important disabilities and death in newborns and infants with lung injury. Although available therapies can relieve the pulmonary hypertension observed in patients that have acquired this disease, there is no treatment that prevents PVD. Currently, no effective therapy directly addresses the pulmonary artery smooth muscle cell (PASMC) hyperplasia and lung fibroblast activation that are the root cause of PVD and distinguish it from adult pulmonary hypertension. Molecules that increase cGMP signaling by stimulating soluble guanylate cyclase (sGC), or by decreasing cGMP degradation, inhibit PVD-like changes in cultured PASMC and fibroblasts. However, they exhibit limited efficacy in preventing PVD in newborns with lung injury. It is suspected that the decreased sGC expression observed in most newborn lung injury models greatly limits the therapeutic promise of these agents. Surprisingly, very little is known about the mechanisms that down-regulate sGC expression in the injured newborn lung and it is unknown whether protection of sGC expression will enhance the salutary activities of sGC agonists. Using a mouse pup model of PVD, active TGF-ß-targeting antibodies, and our recently developed method to isolate peripheral lung mouse pup vascular cells, we determined that TGF-ß down-regulates sGC expression in the injured lung and PASMC, causes PASMC dedifferentiation, and decreases pulmonary microvascular development and alveolarization. Moreover, using sGCa1 knock out mouse pups and our new techniques to quantify peripheral lung fibroblast myogenic activation and alveolarization, we recently determined that decreased sGC activity in itself causes PVD, stimulates lung myofibroblast conversion, and inhibits alveolarization in the setting of very mild lung injury. Based on these results, we speculate that TGF-ß- and sGC-signaling crosstalk disrupts pulmonary development in the injured newborn lung and therefore presents a new therapeutic target to prevent PVD. The central hypothesis of this project is that inhibiting TGF-ß-regulated sGC down-regulation in the injured newborn lung will promote cGMP-stimulated PASMC and lung fibroblast differentiation, and improve pulmonary development. In Aim 1, we propose to identify for the first time the intracellular pathways through which TGF-ß down-regulates sGC expression in mouse pup PASMC to identify new therapeutic targets. In Aim 2, we will test how down-regulated sGC expression controls TGF-ß-mediated mouse pup PASMC and lung fibroblast phenotype switching indicative of PVD. In Aim 3, we will determine how rescuing sGC expression through TGF-ß inhibition potentiates the protective activity of sGC agonists in preventing PVD. Successful completion of this project will identify new mechanisms that down-regulate sGC signaling and promote rapid development of sGC-rescue therapies that improve pulmonary maturation during lung injury and prevent PVD.