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: 7263532
• 负责人: ELENA TOURKINA
• 金额: $ 11.21万
• 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/7263532
• 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; Condition; 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; Numbers; Patients; Peptides; Process; Protein Overexpression; 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; immune function; improved; in vivo; indium-bleomycin; macrophage; mouse model; novel; 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）：我们的长期目标是为硬皮病肺病和其他涉及肺纤维化的疾病开发新的治疗方法。目前还没有有效的治疗方法。初步研究发现，caveolin-1是一种调节胶原蛋白表达的信号分子，因此是这类治疗的一个突出靶点。事实上，当使用博来霉素诱导小鼠肺部疾病时，用小窝蛋白-1激动剂肽进行全身治疗可根据几个标准显著改善病情。虽然这些积极作用可能直接来自于胶原蛋白表达的抑制，但也很有可能是小窝蛋白-1通过抑制炎症起作用，因为组织损伤、炎症和胶原蛋白过度表达的过程在空间和时间上是如此交织在一起，以至于很难确定一个是先行的，或者这些对肺部的损害是否会不断地相互加剧。因此，我们将测试