Rho-Kinase Pathway in Pulmonary Fibrosis

描述（由申请方提供）：特发性肺纤维化（IPF）是一种进行性和致死性疾病过程，没有任何药物治疗被证明明确有效地改变疾病进展或死亡率。成功发现IPF药物的两个主要障碍是：（1）鉴定靶向促进/维持促纤维化细胞表型的分子/信号通路的候选药物;（2）鉴定可靠的动物模型以测试候选药物。我们的初步数据支持Rhokinase（ROCK）通路在调节肌成纤维细胞活化和收缩性中的关键作用。当在博莱霉素诱导的小鼠肺损伤的纤维化阶段给药时，抑制ROCK活性的药理学药物介导抗纤维化作用。我们还提供了体内证据，表明该途径在患有IPF的人类受试者的肺中被激活。最近的证据支持ROCK在涉及其他器官系统的纤维化中在NADPH氧化酶-4（Nox 4）的表达中发挥作用。我们最近的研究表明，Nox 4的活化在肌成纤维细胞活化和肺损伤的纤维化反应中起着重要作用。我们在老年小鼠中建立了临床前动物模型，证明了对肺损伤的持续/进行性纤维化反应，这种反应更类似于IPF的临床表型。在这项资助提案中，我们专注于在这种老化的肺纤维化小鼠模型和人类IPF细胞/组织中进一步验证ROCK通路，最终目标是成功临床翻译至少一种靶向ROCK通路的药物。我们的具体目标是：（1）在IPF衍生的肌成纤维细胞的离体模型中的ROCK激活/调节，并研究该途径与Nox 4激活的串扰;和（2）验证ROCK抑制剂在持续性/进行性肺纤维化的老化模型中的功效。该研究项目非常适合汇集多学科团队，其共同目的是创新药物发现和识别新型动物模型，以测试候选药物的功效。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease process without any drug therapies proven to be unequivocally effective in modifying disease progression or mortality. Two major impediments to successful drug discovery in IPF are: (1) identification of candidate drugs that target molecular/signaling pathways responsible for promotion/maintenance of pro-fibrotic cellular phenotypes; and (2) identification of reliable animal models to test candidate drugs. Our preliminary data support a critical role for the Rhokinase (ROCK) pathway for regulation of myofibroblast activation and contractility. Pharmacologic agents that inhibit ROCK activity mediate anti-fibrotic effects when the drug is administered during the fibrotic phase of bleomycin-induced lung injury in mice. We also provide in-vivo evidence that this pathway is activated in lungs of human subjects with IPF. Recent evidence supports a role for ROCK in the expression of NADPH oxidase-4 (Nox4) in fibrosis involving other organ systems. Our recent studies indicate an essential role for Nox4 activation in myofibroblast activation and fibrogenic respones to lung injury. We have generated preclinical animal models in aged mice that demonstrates a persistent/progressive fibrotic response to lung injury, a response that is more akin to the clinical phenotype of IPF. In this grant proposal, we focus on further robust validation ofthe ROCK pathway in this aging murine model of pulmonary fibrosis and in human IPF cells/tissues with the eventual goal of successful clinical translation of at least one drug that targets the ROCK pathway. Our specific aims are to: (1) Validate ROCK activation/regulation in ex-vivo models of IPF-derived myofibroblasts and study crosstalk ofthis pathway with Nox4 activation; and (2) Validation the efficacy of ROCK inhibitors in an aging model of persistent/progressive lung fibrosis. This research project is ideally suited for bringing together multi-disciplinary teams with a common purpose of innovative drug discovery and identification of novel animal models to test efficacy of candidate drugs.