Molecular Interventions for pulmonary fibrosis

描述(由申请人提供)：肺纤维化是导致大量儿童和成人肺部疾病的发病率和死亡率的原因。目前还没有被批准的治疗纤维性疾病的药物，强调迫切需要找到新的有效的治疗方法。这项建议将确定在小鼠和人类纤维性肺疾病中介导肺纤维增殖的信号通路。我们实验室的数据已经确定了Pisk/mTORCI信号通路在过度表达转化生长因子-a(TGFa)的转基因小鼠肺纤维化中的主要作用。目前的应用验证了这样的假设，即肺纤维化是通过激活PI3K和MAPK信号通路而介导的，这些信号通路通过mTORCI下游的S6核糖体蛋白激酶(P70S6K)汇聚。我们建议在体内使用TGFa驱动的转基因纤维化模型单独或联合测试上述信号通路的药物抑制剂，以确定既可以防止进展又可以逆转已建立和发展的纤维化病变的策略。我们将给目前正在进行临床肿瘤学试验的小鼠使用药物抑制剂。我们还将在特发性肺纤维化样本中验证ERK、Akt和p70S6K信号通路激活的生物标志物。聚集在一起进行这项研究的研究人员是一个多学科团队，在完成这项建议所需的多个学科方面拥有广泛的专业知识，包括细胞信号通路、蛋白质生物化学和肺生理学。这些研究将产生临床前数据，这些数据将确定新的抗纤维增殖药物，并支持未来导致肺纤维化的疾病的临床试验。相关性(见说明书)：该提案将确定介导肺纤维化的靶向信号通路。长期目标是产生临床前数据，这些数据将确定目前正在进行临床肿瘤学试验的特定药物信号通路抑制剂，这些药物可用于未来对人类纤维性肺疾病的研究。

DESCRIPTION (provided by applicant): Pulmonary fibrosis is responsible for morbidity and mortality in a large number of pediatric and adult lung disorders. Currently there are no approved medical treatments for fibrotic disease emphasizing the urgency of identifying novel and effective therapies. This proposal will identify signaling pathways mediating pulmonary fibroproliferation in both mouse and human fibrotic lung disease. Data from our laboratory has identified a primary role for the PiSK/mTORCI signaling pathways in mediating pulmonary fibrosis in transgenic mice over-expressing transforming growth factor-a (TGFa). The current application tests the hypothesis that pulmonary fibrosis is mediated through activation of PI3K and MAPK signaling pathways converging through the S6 ribosomal protein kinase (p70S6K) downstream of mTORCI We propose to test pharmacologic inhibitors for the above signaling pathways alone or in combination in vivo using the TGFa- driven transgenic fibrosis model to determine strategies which will both prevent the progression as well as reverse established and developing fibrotic lesions. We will administer pharmacologic inhibitors to mice that are currently in clinical oncology trials. We will also validate biomarkers of signaling pathway activation for the ERK, Akt and p70S6K pathway in idiopathic pulmonary fibrosis samples. The investigators assembled to perform the studies in this proposal are a multidisciplinary team with extensive expertise in a number of disciplines necessary to complete this proposal including cell signaling pathways, protein biochemistry and pulmonary physiology. These studies will generate preclinical data which will identify novel anti- fibroproliferative drugs and support future clinical trials in disorders causing pulmonary fibrosis. RELEVANCE (See instructions): This proposal will identify targetable signaling pathways mediating pulmonary fibrosis. The long term goal is to produce pre-clinical data which will identify specific pharmacologic signaling pathway inhibitors currently In clinical oncology trials that can be utilized for future studies in human fibrotic lung disease.