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

基本信息

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
项目类别：
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

项目摘要

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用于硬皮病肺疾病和其他涉及肺纤维化的疾病的新型治疗方法。目前，没有有效的疗法。初步研究已将口腔素-1鉴定为调节胶原蛋白表达的信号分子，因此是这种疗法的杰出靶标。实际上，当使用博来霉素诱导小鼠肺病时，可爱素-1激动剂肽的全身治疗会导致几个标准的急剧改善。 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.因此，我们将测试假设在体内上requlatinq Caveolin-1表达/活性将通过直接抑制胶原蛋白表达和/或抑制炎症来保护肺纤维化。具体而言，我们将：1）优化由病毒载体编码的小窝蛋白-1激动剂肽和全长小窝蛋白-1的递送。一旦我们优化了小窝蛋白-1激动剂肽和全长小窝蛋白-1的递送，我们将：2）确定在体内中上调小窝蛋白-1表达/活性是否直接抑制肌纤维细胞的分化（导致纤维性肺部表达中的胶原性表达的细胞），以及在纤维性肺部表达中是否表达出来，以及3），以及3），以及3），以及3），以及3），以及3），以及3），以及3），以及3）和3）。巨噬细胞和PMN体外和体内改变了免疫功能。这些研究的成功完成将要求我在该K01应用的三个靶向区域中进行了良好的训练（使用动物模型，体内基因的病毒输送，免疫学），并将证明，在体内caveolin-1表达/活性上调可能是scleroderma肺疾病的有效治疗。关于与公共卫生相关的LAV语言 - 目前尚无对组织变得僵硬或纤维化的有效治疗方法，使患者很难呼吸。使用纤维化肺部疾病的小鼠模型，我们已经表明，增加称为Caveolin-1的蛋白质的活性可提供可观的好处。我们将通过找到最佳的治疗条件并通过简单地通过阻止免疫系统过度活跃的细胞或通过这两种机制来阻止组织损伤来确定治疗方法来进一步探索口腔素-1作为肺纤维化的治疗方法。