Mechanisms of proteasomal regulation of fibrosis

蛋白酶体调节纤维化的机制

• 批准号: 7931068
• 负责人: GR Scott Budinger
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931068
• 关键词: Adult Respiratory Distress Syndrome; Attenuated; Autoimmune Process; Binding; Bleomycin; Bortezomib; Cell Culture System; Cell Nucleus; Cessation of life; Cicatrix; Collagen; Complex; Consensus Sequence; DNA; Data; Development; Disease; EP300 gene; Endothelium; Epithelium; FDA approved; Fibroblasts; Fibrosis; Gene Targeting; Genes; Genetic Transcription; Hamman-Rich syndrome; Human; Injury; Integrins; Lung; Lung diseases; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Mothers; Mus; Myofibroblast; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phosphorylation; Prevention; Promoter Regions; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Pulmonary Fibrosis; Regulation; Research Personnel; Respiratory Failure; Sarcoidosis; Scleroderma; Series; Skin; Staging; Study models; System; Therapeutic; Toxic effect; Transforming Growth Factor beta; Ubiquitin; Vascular Diseases; Veterans; attenuation; base; cytokine; gene therapy; human TGFB1 protein; inhibitor/antagonist; innovation; insight; lung development; mouse model; novel therapeutics; prevent; receptor; research study; response; therapeutic target; tool; treatment strategy

DESCRIPTION (provided by applicant): ABSTRACT A number of pharmacologic or genetic interventions have been shown to prevent the development of fibrosis following the intratracheal administration of bleomycin, a commonly used model for the study of lung fibrosis. These studies have provided important mechanistic insights into the development of pulmonary fibrosis and have identified both transforming growth factor-beta (TGF-2) and peroxsome prolifeator- activated receptor-gamma (PPAR3) as important mediators of fibrosis. In our preliminary data, we observed that the administration of a proteasome inhibitor to mice 8 days after the administration of bleomycin resulted in marked attenuation of lung fibrosis. Similar protection was observed in a bleomycin induced skin fibrosis model of scleroderma. Additional preliminary data suggest that proteasomal inhibition results in increased abundance and activity of PPAR3, which functions as an inhibitor of TGF-2. We hypothesize that the administration of proteasomal inhibitors prevents the ubiquitin-mediated degradation of PPAR-3 in normal human lung fibroblasts and in the mouse lung thereby inhibiting the transcriptional response to active TGF-2 and attenuating fibrosis. We have generated three interrelated specific aims to identify the molecular mechanisms by which PPAR3 is degraded and by which this degradation is accelerated in the presence of TGF-2. Aim 1. Is PPAR-3 required for inhibition of the transcriptional response to active TGF-2 induced by proteasomal inhibition in normal human lung fibroblasts? Aim 2. How is PPAR-3 targeted for proteasomal degradation in normal human lung fibroblasts? Aim 3. Does the bortezomib- mediated increase in the protein abundance of PPAR3 prevent the development of lung fibrosis in mice treated with bleomycin downstream of the activation of TGF- 21? This application represents a highly innovative effort that employs molecular tools in cell culture systems and sophisticated mouse models to elucidate the mechanisms by which proteasomal inhibition might prevent the development of pulmonary fibrosis. Our preliminary data support the feasibility of the proposed experiments and provide support for our focus on the ubiquitin-proteasomal system's regulation of PPAR3. PUBLIC HEALTH RELEVANCE: Many lung diseases including the Acute Respiratory Distress Syndrome, Idiopathic Pulmonary Fibrosis, Sarcoidosis, Scleroderma and a variety of others cause scarring (fibrosis) of the lung that if progressive can result in respiratory failure or death. In this proposal, the investigators have found that the administration of an FDA approved medication used to treat some cancers, bortezomib, is effective at preventing the development of lung and skin fibrosis in mice. They propose a series of experiments to determine how this medication protects against fibrosis. Early data from these experiments suggest that bortezomib increases the concentration of a key protein involved in the development of fibrosis. Targeting this protein would represent a new and novel therapeutic strategy for the treatment of Veterans with lung fibrosis.

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