过氧化物酶增殖物激活受体PPARγ促进肺动脉平滑肌细胞Caveolin-1蛋白降解的作用和机制研究

肺动脉高压（PH）是一种进展迅速、致死率高的心肺血管综合征。由于致病机制不明，目前的治疗药物无法从根本上治愈疾病。近年来，噻唑烷二酮类过氧化物酶增殖物激活受体γ（PPARγ）激动剂（如罗格列酮和吡格列酮）为PH的临床治疗带来新的希望。我们和其他课题组的研究发现，罗格列酮和吡格列酮对低氧性PH动物模型具有良好的治疗效果，可显著抑制PH伴随的肺动脉平滑肌异常增生与重塑。我们的研究进一步发现，PPARγ活化促进小窝蛋白Caveolin-1的蛋白降解是抑制低氧诱导的肺动脉平滑肌细胞增殖的重要基础，然而其分子机制尚不明确。因此，在本研究中，我们将在前期研究基础上，进一步系统研究PPARγ活化促进Caveolin-1蛋白经由溶酶体降解的分子机制。该研究将丰富我们对于PPARγ激动剂作用靶点的认识，并为更好的评价该类药物治疗肺动脉高压的潜力提供重要的理论依据。

Pulmonary hypertension (PH) is a highly risky cardiopulmonary syndrome with complicated disease mechanisms and poor prognosis. So far, the existed therapy against PH can only minimize the disease phenotypes, however, cannot cure the disease from the molecular basis. Recent studies from our and others’ labs have both shown that the Thiazolidinediones (TZDs) class agonists (Rosiglitazone and Pioglitazone) of peroxisome proliferator-activated receptor γ (PPARγ) have achieved breakthrough progression in the treatment of experimental PH animal models, by normalizing the excessive thickening and remodeling of pulmonary arterial smooth muscle and the proliferation of pulmonary arterial smooth muscle cells (PASMCs). We further reported that PPARγ activation can inhibit the hypoxia-induced expression of Caveolin-1 by promoting its protein degradation, thus affects the intracellular calcium homeostasis and inhibits the PASMCs proliferation. Therefore, based on previous research, in this study, by comprehensively use of transgenic knockout mice models (e.g. Caveolin-1), molecular and cell biology strategies, we will continue to determine the detail molecular mechanisms how PPARγ activation promotes Caveolin-1 protein degradation. Our research mainly focuses on three specific aims: 1) Determine the role of PPARγ activation on the formation, distribution and plasma localization of caveolae in PASMCs; 2) Determine the detail molecular mechanisms how PPARγ activation promotes Caveolin-1 protein degradation through lysosome system; and 3) Explore the role of Caveolin-1 in PPARγ agonist-mediated protection of experimental PH in animal models.