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发病率和死亡率的原因。目前还没有批准的用于纤维化疾病的药物治疗，强调了确定新的和有效的疗法的紧迫性。该提案将确定介导小鼠和人类纤维化肺病中肺纤维增生的信号通路。来自我们实验室的数据已经确定了PiSK/mTORCI信号通路在介导过表达转化生长因子-α（TGF α）的转基因小鼠中的肺纤维化中的主要作用。本申请测试了肺纤维化是通过PI 3 K和MAPK信号传导途径的激活介导的假设，所述PI 3 K和MAPK信号传导途径通过mTORCI下游的S6核糖体蛋白激酶（p70 S6 K）会聚。驱动的转基因纤维化模型，以确定既能预防进展又能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施用药理学抑制剂。我们还将验证特发性肺纤维化样本中ERK、Akt和p70 S6 K通路的信号通路激活的生物标志物。执行本提案中研究的研究者是一个多学科团队，在完成本提案所需的多个学科中具有广泛的专业知识，包括细胞信号传导通路、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生药物，并支持未来在引起肺纤维化的疾病中的临床试验。相关性（见说明）：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在临床肿瘤学试验中可用于人类纤维化肺病未来研究的特定药理学信号通路抑制剂。

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.