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: 7878837
• 负责人: ELENA TOURKINA
• 金额: $ 12.05万
• 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/7878837
• 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治疗硬皮病、肺部疾病和其他涉及肺纤维化的疾病的新疗法。目前，还没有有效的治疗方法。初步研究已经确定小窝蛋白-1是一种信号分子，调节胶原蛋白的表达，因此是此类治疗的杰出靶点。事实上，当使用博莱霉素诱导小鼠肺部疾病时，使用小凹-1激动肽的全身治疗从几个标准上导致了显著的改善。虽然这些积极作用可能直接来自于抑制胶原蛋白的表达，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交织在一起，极难确定是一个先于其他过程，还是这些对肺的侮辱是否不断加剧，因此小窝蛋白-1也很可能通过抑制炎症发挥作用。因此，我们将测试 假设体内上调小窝蛋白-1的表达/活性将通过直接抑制胶原表达和/或通过抑制炎症来提供对肺纤维化的保护。具体地说，我们将：1)优化病毒载体编码的小窝蛋白-1激动肽和全长小窝蛋白-1的递送。一旦我们优化了小凹-1激动肽和全长小凹-1的递送方式，我们将：2)确定在体内上调小凹-1的表达/活性是否直接抑制肌成纤维细胞(纤维性肺部疾病中导致胶原过度表达的细胞)的分化及其胶原的表达；3)确定上调小窝-1在体外和体内的巨噬细胞和中性粒细胞中的表达/活性是否改变免疫功能。成功完成这些研究将需要我在K01应用程序的三个目标领域(动物模型的使用、体内基因的病毒传递、免疫学)方面接受过良好的培训，并将证明在体内上调小窝蛋白-1的表达/活性可能是治疗硬皮病肺部疾病的有效方法。关于与公共健康相关的LAV语言--目前还没有有效的治疗方法来治疗肺部疾病，这些疾病的组织变得僵硬或纤维化，使患者呼吸非常困难。通过使用纤维化肺部疾病的小鼠模型，我们已经证明，增加一种名为小窝蛋白-1的蛋白质的活性可以提供实质性的好处。我们将进一步探索小窝蛋白-1作为肺纤维化的治疗方法，找到最佳的治疗条件，并确定治疗是通过简单地阻断组织的僵硬，通过阻断免疫系统过度活跃的细胞引起的组织损伤，还是通过这两种机制来发挥作用。