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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.

描述（由申请人提供）：我们的研究重点是识别和测试破坏血管 cGMP 信号传导的新机制，以开发保护受损新生肺的肺发育的新疗法。小儿肺血管疾病 (PVD) 会导致肺损伤的新生儿和婴儿严重残疾和死亡。尽管现有的治疗方法可以缓解患有这种疾病的患者中观察到的肺动脉高压，但没有任何治疗方法可以预防 PVD。目前，尚无有效的治疗方法可以直接解决肺动脉平滑肌细胞（PASMC）增生和肺成纤维细胞活化问题，而肺动脉平滑肌细胞（PASMC）增生和肺成纤维细胞活化是PVD的根本原因，并将其与成人肺动脉高压区分开来。通过刺激可溶性鸟苷酸环化酶 (sGC) 或减少 cGMP 降解来增加 cGMP 信号传导的分子，可抑制培养的 PASMC 和成纤维细胞中的 PVD 样变化。然而，它们在预防肺损伤新生儿的 PVD 方面的功效有限。人们怀疑，在大多数新生儿肺损伤模型中观察到的 sGC 表达降低极大地限制了这些药物的治疗前景。令人惊讶的是，我们对受损新生肺中 sGC 表达下调的机制知之甚少，并且尚不清楚保护 sGC 表达是否会增强 sGC 激动剂的有益活性。使用 PVD 小鼠幼模型、活性 TGF-β 靶向抗体以及我们最近开发的分离小鼠幼仔外周血管细胞的方法，我们确定 TGF-β 下调受损肺和 PASMC 中 sGC 的表达，导致 PASMC 去分化，并减少肺微血管发育和肺泡化。此外，使用 sGCa1 敲除小鼠幼崽和我们的新技术来量化外周肺成纤维细胞肌源性激活和肺泡化，我们最近确定 sGC 活性降低本身会导致 PVD，刺激肺肌成纤维细胞转化，并在非常轻微的肺损伤的情况下抑制肺泡化。基于这些结果，我们推测 TGF-β- 和 sGC 信号传导串扰会扰乱受损新生肺的肺发育，因此提出了预防 PVD 的新治疗靶点。该项目的中心假设是，抑制受损新生肺中 TGF-β 调节的 sGC 下调将促进 cGMP 刺激的 PASMC 和肺成纤维细胞分化，并改善肺部发育。在目标 1 中，我们建议首次确定 TGF-β 下调小鼠幼崽 PASMC 中 sGC 表达的细胞内途径，以确定新的治疗靶点。在目标 2 中，我们将测试下调 sGC 表达如何控制 TGF-β 介导的小鼠幼崽 PASMC 和指示 PVD 的肺成纤维细胞表型转换。在目标 3 中，我们将确定如何通过抑制 TGF-β 来挽救 sGC 表达，从而增强 sGC 激动剂预防 PVD 的保护活性。该项目的成功完成将确定下调 sGC 信号传导的新机制，并促进 sGC 救援疗法的快速发展，从而改善肺损伤期间的肺成熟并预防 PVD。