权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of PPARa on renal fibrosis

PPARa 对肾纤维化的作用

基本信息

批准号：
8635589
负责人：
DIDIER PORTILLA
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We propose to examine the relationship between substrate oxidation, lipotoxicity and proximal tubule cell death. We have shown that activation of PPAR using a ligand, or by increased expression of PPAR in the proximal tubule using transgenic mice ameliorates kidney function in the ischemia reperfusion injury (IRI), and cisplatin model of nephrotoxicity. Our preliminary studies demonstrate a significant reduction in proximal tubule cell death and reduced interstitial fibrosis in PPAR Tg mice subjected to both unilateral ischemia and Unilateral Ureteral Obstruction (UUO), when compared to wild type mice. Our central hypothesis predicts that increased expression and activity of proximal tubule and pericyte PPAR interdict tubulo-interstitial inflammation and renal fibrosis, a hallmark of the progression from Acute to Chronic Kidney Disease (CKD). Specific Aim 1 is to determine whether increased proximal tubule (PT)-PPAR interferes with tubulo-interstitial fibrosis. We hypothesize that increased expression of proximal tubule PPAR attenuates renal fibrosis. We will use wild type, genetically deficient PPAR mice, and PPAR transgenic mice and two animal models of renal fibrosis to determine if increased fatty acid oxidation, lipoprotein lipase activity, and increased autophagy contribute to reduced lipotoxicity and prevent proximal tubule cell death in models of renal fibrosis. Specific Aim 2 is to determine cellular mechanisms by which pericyte PPAR influences pericyte to myofibroblast transition. We propose to isolate and culture mouse kidney pericytes in order to 1) determine the effects of PPAR overexpression on the pericyte-to-myofibroblast transition, 2) determine whether the PPAR-mediated increase in fatty acid oxidation, reduced neutral lipid accumulation, and/or changes to pericyte adipogenesis prevent the pericyte conversion to myofibroblasts in vitro, and 3) to determine the role of PPAR deficiency on the transition of pericytes to myofibroblasts. Altogether, these studies will further advance our knowledge of pericyte metabolism and function, which should provide additional therapeutic targets to prevent the progression of AKI to CKD.

描述(由申请人提供)：我们建议研究底物氧化、脂毒性和近曲小管细胞死亡之间的关系。我们已经证明，使用配体激活PPAR，或通过转基因小鼠增加近端小管中PPAR的表达，可以改善缺血再灌注损伤(IRI)和顺铂肾毒性模型的肾功能。我们的初步研究表明，与野生型小鼠相比，单侧缺血和单侧输尿管梗阻(UUO)的PPAR TG小鼠近端小管细胞死亡和间质纤维化显著减少。我们的中心假说预测，近端小管和周细胞PPAR的表达和活性增加阻止了肾小管间质炎症和肾纤维化，这是急性肾脏疾病(CKD)向慢性肾脏疾病(CKD)进展的标志。具体目的1是确定近端小管(PT)-PPAR增加是否干扰肾小管间质纤维化。我们假设近曲小管PPAR的表达增加可以减轻肾纤维化。我们将使用野生型、遗传缺陷的PPAR小鼠、PPAR转基因小鼠和两种肾纤维化动物模型来确定在肾纤维化模型中，增加脂肪酸氧化、脂蛋白脂酶活性和增加自噬是否有助于降低脂毒性和防止近端小管细胞死亡。具体目的2是确定周细胞PPAR影响周细胞向肌成纤维细胞转化的细胞机制。我们建议分离和培养小鼠肾周细胞，以1)确定PPAR过表达对周细胞向肌成纤维细胞转化的影响，2)确定PPAR介导的脂肪酸氧化增加、中性脂肪堆积减少和/或周细胞脂肪生成的改变是否在体外阻止周细胞向肌成纤维细胞的转化，以及3)确定PPAR缺陷在周细胞向肌成纤维细胞转化中的作用。总之，这些研究将进一步促进我们对周细胞代谢和功能的了解，这将为防止AKI进展为CKD提供额外的治疗靶点。