Anti-fibrotic and anti-inflammatory roles of caveolin-1 in lung disease

Caveolin-1 在肺部疾病中的抗纤维化和抗炎作用

• 批准号: 7643961
• 负责人: ELENA TOURKINA
• 金额: $ 11.76万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643961
• 关键词: Adenovirus Vector; Adenoviruses; Agonist; Air; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Behavior; Biological Assay; Bleomycin; Breathing; Caveolins; Cells; Collagen; Dependovirus; Disease; Dose; Ensure; Fibroblasts; Fibrosis; Flow Cytometry; Goals; Hand; Human; Immune system; Immunohistochemistry; Immunology; In Vitro; Inflammation; Invaded; Language; Length; Lung; Lung diseases; Methods; Morphology; Mus; Myofibroblast; Patients; Peptides; Process; Proteins; Public Health; Regulation; Role; Route; Scleroderma; Signaling Molecule; Smooth Muscle Actin Staining Method; Structure of parenchyma of lung; Testing; Time; Tissues; Training; Trichrome stain; Viral Vector; Weight; Western Blotting; Work; caveolin 1; effective therapy; immune function; improved; in vivo; indium-bleomycin; macrophage; mouse model; novel; overexpression; research study; skills; tissue processing; treatment effect; viral gene delivery

DESCRIPTION (provided by applicant): Our long-term goal is to develop novel treatments for scleroderma lung disease and other diseases involving lung fibrosis. Currently, there are no effective therapies. Preliminary Studies have identified caveolin-1 as a signaling molecule that regulates collagen expression and therefore is an outstanding target for such therapies. Indeed, when lung disease is induced in mice using bleomycin, systemic treatment with a caveolin-1 agonist peptide causes a dramatic improvement by several criteria. While these positive effects may result directly from the inhibition of collagen expression, it is also quite possible that caveolin-1 is acting by inhibiting inflammation, given that the processes of tissue damage, inflammation, and overexpression of collagen are so intertwined in space and time that it is extremely difficult to determine whether one precedes the others or whether these insults to the lung continually exacerbate each other. Therefore, we will test the hypothesis that uprequlatinq caveolin-1 expression/activity in vivo will provide protection against lung fibrosis by directly inhibiting collagen expression and/or by inhibiting inflammation. Specifically we will: 1) Optimize the delivery of the caveolin-1 agonist peptide and full-length caveolin-1 encoded by viral vectors. Once we have optimized the delivery of caveolin-1 agonist peptide and full-length caveolin-1, we will: 2) Determine whether upregulating caveolin-1 expression/activity in vivo directly inhibits the differentiation of myofibrpblasts (the cells responsible for the over-expression of collagen in fibrotic lung diseases) and their expression of collagen, and 3) Determine whether up-regulating caveolin-1 expression/activity in macrophages and PMNs in vitro and in vivo alters immune functions. Successful completion of these studies will require that I become well-trained in the three targeted areas of this K01 application (use of animal models, viral delivery of genes in vivo, immunology) and will demonstrate that upregulating caveolin-1 expression/activity in vivo is likely to be an effective therapy for scleroderma lung disease. Lav language regarding relevance to public health - There are currently no effective treatments for lung diseases in which the tissue becomes stiff or fibrotic, making it very difficult for the patient to breathe. Using a mouse model of fibrotic lung disease, we have already shown that increasing the activity of a protein known as caveolin-1 provides substantial benefit. We will further explore caveolin-1 as a treatment for lung fibrosis by finding the optimal treatment conditions and by determining whether the treatment works by simply blocking the stiffening of the tissue, by blocking tissue damage caused by overactive cells from the immune system, or through both of these mechanisms.

描述（由申请人提供）：我们的长期目标是开发针对硬皮病肺病和其他涉及肺纤维化的疾病的新疗法。目前，尚无有效的治疗方法。初步研究已确定 Caveolin-1 是调节胶原蛋白表达的信号分子，因此是此类疗法的杰出靶点。事实上，当使用博来霉素在小鼠中诱发肺部疾病时，用 Caveolin-1 激动剂肽进行全身治疗可在几个标准上引起显着的改善。虽然这些积极作用可能直接来自抑制胶原蛋白表达，但鉴于组织损伤、炎症和胶原蛋白过度表达的过程在空间和时间上如此交织在一起，因此很难确定其中一个先于其他过程，或者这些对肺部的损害是否不断相互加剧，因此caveolin-1也很可能通过抑制炎症发挥作用。因此，我们将测试 假设体内上调 Caveolin-1 表达/活性将通过直接抑制胶原蛋白表达和/或抑制炎症来提供针对肺纤维化的保护。具体来说，我们将： 1) 优化由病毒载体编码的caveolin-1激动剂肽和全长caveolin-1的递送。一旦我们优化了caveolin-1激动剂肽和全长caveolin-1的递送，我们将：2)确定体内上调caveolin-1表达/活性是否直接抑制肌成纤维细胞(负责纤维化肺疾病中胶原蛋白过度表达的细胞)的分化及其胶原蛋白表达，以及3)确定在体内上调caveolin-1表达/活性是否 巨噬细胞和 PMN 在体外和体内都会改变免疫功能。成功完成这些研究需要我在 K01 应用的三个目标领域（动物模型的使用、体内基因的病毒传递、免疫学）接受良好的培训，并将证明上调 Caveolin-1 体内表达/活性可能是硬皮病肺部疾病的有效治疗方法。 Lav 语言与公共卫生的相关性 - 目前尚无有效的治疗方法来治疗肺部疾病，这些疾病的组织会变得僵硬或纤维化，使患者呼吸非常困难。使用纤维化肺疾病的小鼠模型，我们已经证明，增加称为 Caveolin-1 的蛋白质的活性可带来显着的益处。我们将进一步探索caveolin-1作为肺纤维化的治疗方法，寻找最佳治疗条件，并确定该治疗是否通过简单地阻止组织僵化、阻止免疫系统过度活跃细胞引起的组织损伤或通过这两种机制起作用。