Targeting Lipogenic and Angiogenic Mediators in Pulmonary Fibrosis

翻译后摘要：由于在肺纤维化（PF）的诊断和治疗方式的主要挑战， 重要的是要继续确定新的和可行的药物靶点，以打击与 疾病我们建议使用传统的分子生物学技术和高通量 脂质组学和蛋白质组学方法，以确定新的蛋白质和脂质生物标志物，并研究其 长期的目标是开发一种有效的治疗PF的策略，这项研究 与国家心肺血液研究所的使命直接相关。的总体目标 拟议的研究是确定新的生物标志物，并研究脂肪生成和血管生成之间的相互作用 最近的证据表明，脂质在PF的治疗中起着重要的作用， PF中的介质，但很少有人知道的整体脂质组成失调的疾病进展。 初步数据表明，脂肪酸合成酶（FATCH），一种重要的脂肪生成酶， 目的1探讨肺纤维化在博莱霉素（BLM）诱导的肺纤维化中的作用 在PF的发病机制，并确定关键的FASN相关的脂质和蛋白质的合作伙伴。初步蛋白质组学 BLM处理的小鼠肺组织分析鉴定了磷脂酰肌醇-3-激酶/蛋白激酶B（PI 3 K/Akt） Wnt（Wingless Integration-1）/β-catenin信号通路是两条最重要的纤维化信号通路， 参与的途径。PI 3 K/Akt和Wnt/β-连环蛋白途径已显示出增强纤维化反应， 我们已经报道了血管内皮生长因子（VEGF）的关键作用，VEGF是血管内皮生长因子的直接靶点。 PI 3 K/Akt通路在纤维化调节中的作用。众所周知，在其他肺部疾病中， 哮喘，并激活乳腺癌和前列腺癌中的Wnt/β-连环蛋白信号。我们假设， 通过调节PI 3 K/Akt、VEGF和Wnt/β-catenin通路发挥其作用。目标2旨在 探讨Wnt/β-catenin和PI 3 K/Akt>VEGF信号通路对Fctin调控的机制 我们正在进行的体内研究表明，FXR抑制剂奥利司他显著抑制了BLM诱导的PF。 BLM诱导的PF。此外，FcG、VEGF和Wnt/β-catenin之间出现了强烈的相互作用， 目的3旨在评估抗纤维化药物如奥利司他是否介导肺纤维化 通过调节PI 3 K/Akt、VEGF和Wnt/β-catenin信号通路，探讨其在肿瘤细胞凋亡中的作用。 开发涉及奥利司他和PI 3 K/Akt、VEGF和Wnt/β-连环蛋白抑制剂的联合治疗方案 途径。这种串扰的研究和相关关键生物标志物的鉴定将是重要的， 增加对PF发病机制的分子机制的理解，并将促进 为这种致命疾病制定潜在的治疗和预防策略。

Abstract: Due to the major challenges in both diagnostic and therapeutic modalities in pulmonary fibrosis (PF), it is important to continue identifying novel and viable drug targets to combat pathogenesis associated with the disease. We propose to use a combination of traditional molecular biology techniques and high-throughput lipidomics and proteomics approaches to identify novel protein and lipid biomarkers, and investigate their contribution to PF. The long-term goal is to develop an effective therapeutic strategy against PF, and this study is directly relevant to the mission of National Heart, Lung and Blood Institute. The overall objective of the proposed study is to identify novel biomarkers and study the interplay between lipogenic and angiogenic mediators that may be targeted for treatment of PF. Recent evidence suggests an important role for lipid mediators in PF, but little is known about the deregulation of overall lipid composition in disease progression. Preliminary data suggests a critical role for fatty acid synthase (FASN), an important lipogenic enzyme associated with lung injury, in bleomycin (BLM)-induced PF. Aim 1 is designed to investigate the role of FASN in the pathogenesis of PF and identify key FASN-associated lipid and protein partners. Preliminary proteomic analysis of BLM-treated mouse lung tissue identified Phosphatidylinositol-3-kinase/Protein Kinase B (PI3K/Akt) and Wnt (Wingless Integration-1)/beta(β)-catenin signaling pathways as the two most important fibrotic pathways involved. PI3K/Akt and Wnt/β-catenin pathways have been shown to potentiate fibrotic response, and we have reported on the critical role of vascular endothelial growth factor (VEGF), a direct target of PI3K/Akt pathway, in regulating fibrosis. FASN is known to regulate VEGF in other lung diseases such as asthma, and activate Wnt/β-catenin signaling in breast and prostate cancers. We hypothesize that FASN exerts its effects in PF by regulating PI3K/Akt>VEGF and Wnt/β-catenin pathways. Aim 2 is designed to investigate the mechanistic effect of Wnt/β-catenin and PI3K/Akt>VEGF signaling on regulation of FASN in BLM-induced PF. Our ongoing in vivo studies demonstrates that FASN inhibitor Orlistat significantly inhibited BLM-induced PF. Furthermore, a strong interplay has emerged between FASN, VEGF and Wnt/β-catenin signaling in PF. Aim 3 is designed to evaluate whether anti-FASN agents such as Orlistat mediate lung fibrosis by regulating PI3K/Akt>VEGF and Wnt/β-catenin signaling pathways, and investigate the potential development of a co-therapy regimen involving Orlistat and inhibitors of the PI3K/Akt>VEGF and Wnt/β-catenin pathways. Investigation of this crosstalk and identification of related key biomarkers will be important for the increased understanding of the molecular mechanisms involved in the pathogenesis of PF and will facilitate development of potential therapeutic and preventive strategies for this fatal disease.