Impact of Oxidative Stress-Regulated Angiogenesis in Pulmonary Fibrosis

氧化应激调节血管生成对肺纤维化的影响

基本信息

批准号：
8078717
负责人：
Neelam Azad
金额：
$ 30.16万
依托单位：
HAMPTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078717
关键词：
1-Phosphatidylinositol 3-Kinase Angiogenesis Inhibitors Animal Model Antioxidants Biological Markers Bleomycin Cell Proliferation Cell Survival Characteristics Collagen Combined Modality Therapy Data Development Disease Environment Enzymes Exposure to Failure Fibroblasts Fibrosis Goals Hamman-Rich syndrome Hypoxia Inducible Factor Link Lung Manganese Superoxide Dismutase Mediating Mediator of activation protein Mission Mitochondria Modality Molecular Molecular Target National Heart, Lung, and Blood Institute Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Pathway interactions Phosphorylation Play Prevention strategy Process Production Protein Isoforms Pulmonary Fibrosis Regulation Reporting Role Signal Pathway Signal Transduction Signal Transduction Pathway Stimulus Testing Therapeutic Tumor Angiogenesis Up-Regulation Vascular Endothelial Cell Vascular Endothelial Growth Factors angiogenesis cell type design hypoxia inducible factor 1 indium-bleomycin kinase inhibitor knockout gene lung injury mimetics neovascularization novel porphyrin a response tetrakis(4-benzoic acid)porphyrin therapeutic effectiveness

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis and aberrant cellular redox state are the hallmarks of the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying these pathologic alterations are poorly understood. Failure to understand and target such critical mechanisms directly limits the effectiveness of the therapeutic efforts against this disease. The long-term goal of this study is to develop an effective therapeutic strategy against pulmonary fibrosis and is directly relevant to the mission of National Heart, Lung and Blood Institute. The overall objective of this proposal is to investigate the contribution of oxidative stress-regulated angiogenesis in the pathogenesis of bleomycin (BLM)-induced pulmonary fibrosis. In spite of a strong positive correlation between the angiogenic mediator vascular endothelial growth factor (VEGF) and pulmonary fibrosis, the role of VEGF in pulmonary fibrosis is poorly understood. Aim 1 is designed to establish the role of VEGF in the pathogenesis of pulmonary fibrosis and test the hypothesis that phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway regulates VEGF via hypoxia inducible factor (HIF)-11 in BLM-induced pulmonary fibrosis. Although pro-angiogenic environment is known to co-exist with progressive fibrosis, the contribution of neovascularization to the progression of fibrosis is understudied. The preliminary data demonstrates a significant increase in angiogenesis in vascular endothelial cells in response to BLM treatment. Aim 2 is designed to establish the involvement of angiogenesis in BLM-induced pulmonary fibrosis and test the hypothesis that angiogenesis during BLM-induced pulmonary fibrosis is dependent, in part, upon Akt mediated upregulation of the angiogenic mediator VEGF. Gene knockout and pharmacological approaches will be used to elucidate the role of Akt and identify its specific isoform(s) involved in the process. Increased oxidative stress have been implicated in lung injury and fibrosis and its inhibition has shown to offer significant protection against pulmonary fibrosis in animal models. Aim 3 is designed to evaluate if antioxidants such as manganese superoxide dismutase (MnSOD) mediate lung fibrosis by regulating the angiogenic (PI3K/Akt->HIF-1->VEGF) pathway. The preliminary data shows that Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP), an MnSOD mimetic, significantly blocked BLM-induced angiogenic and fibrogenic response. We hypothesize that MnTBAP might be effective in suppressing pulmonary fibrosis by modulating the angiogenic pathway. The proposed study will be important for the increased understanding of the molecular mechanisms involved in the pathogenesis of pulmonary fibrosis. The study will also aid in identifying key molecular targets, which may serve as novel biomarkers and provide alternative avenues for the development of potential therapeutic and preventive strategies for this fatal disease. PUBLIC HEALTH RELEVANCE: The proposed study will explore the modalities that dictate pathogenesis of pulmonary fibrosis. The overall objective of this proposal is to elucidate the role of some of the characteristic features such as angiogenesis and oxidative stress that have been implicated in pulmonary fibrosis but are understudied. The idea of angiogenic mediators regulating lung fibrosis represents a paradigm shift in the present understanding of this disease, and will pave way for tackling fibrosis using a new and different approach. The proposed study will be important not only to the increased understanding of the molecular mechanisms of lung fibrosis but also in the development of potential therapeutic and preventive strategies for this fatal disease.

描述（由申请人提供）：血管生成和异常的细胞氧化还原状态是特发性肺纤维化（IPF）发病机制的标志，但这些病理改变背后的机制尚不清楚。未能理解和瞄准这些关键机制直接限制了针对这种疾病的治疗努力的有效性。这项研究的长期目标是开发一种有效的肺纤维化治疗策略，与国家心肺血液研究所的使命直接相关。该提案的总体目标是研究氧化应激调节的血管生成在博来霉素（BLM）诱导的肺纤维化发病机制中的作用。尽管血管生成介质血管内皮生长因子（VEGF）与肺纤维化之间存在很强的正相关性，但人们对VEGF在肺纤维化中的作用知之甚少。目的 1 旨在建立 VEGF 在肺纤维化发病机制中的作用，并检验磷脂酰肌醇 3 激酶 (PI3K)/Akt 信号通路在 BLM 诱导的肺纤维化中通过缺氧诱导因子 (HIF)-11 调节 VEGF 的假设。尽管已知促血管生成环境与进行性纤维化共存，但新血管形成对纤维化进展的贡献尚未得到充分研究。初步数据表明，BLM 治疗后血管内皮细胞的血管生成显着增加。目标 2 旨在确定 BLM 诱导的肺纤维化中血管生成的参与，并测试 BLM 诱导的肺纤维化过程中血管生成部分依赖于 Akt 介导的血管生成介质 VEGF 上调的假设。基因敲除和药理学方法将用于阐明 Akt 的作用并鉴定其参与该过程的特定亚型。氧化应激的增加与肺损伤和纤维化有关，在动物模型中，氧化应激的抑制已显示出对肺纤维化的显着保护作用。目标 3 旨在评估锰超氧化物歧化酶 (MnSOD) 等抗氧化剂是否通过调节血管生成 (PI3K/Akt->HIF-1->VEGF) 途径介导肺纤维化。初步数据显示，Mn(III)四(4-苯甲酸)卟啉 (MnTBAP)（一种 MnSOD 模拟物）可显着阻断 BLM 诱导的血管生成和纤维生成反应。我们假设 MnTBAP 可能通过调节血管生成途径有效抑制肺纤维化。拟议的研究对于加深对肺纤维化发病机制的分子机制的了解非常重要。该研究还将有助于确定关键分子靶标，这些靶标可以作为新型生物标志物，并为开发这种致命疾病的潜在治疗和预防策略提供替代途径。公共卫生相关性：拟议的研究将探讨决定肺纤维化发病机制的方式。该提案的总体目标是阐明一些特征的作用，例如血管生成和氧化应激，这些特征与肺纤维化有关，但尚未得到充分研究。血管生成介质调节肺纤维化的想法代表了目前对该疾病理解的范式转变，并将为使用新的不同方法应对纤维化铺平道路。拟议的研究不仅对于加深对肺纤维化分子机制的了解很重要，而且对于开发这种致命疾病的潜在治疗和预防策略也很重要。