Investigation of Nephrotic Syndrome

描述（由申请人提供）：肾病综合征是肾衰竭的主要原因，患有这种疾病的患者会出现大量蛋白尿和血浆脂质（甘油三酯和胆固醇）水平升高。主要研究者/申请人的近期目标是详细研究肾病综合征中高胆红素血症发生的机制。PI的长期目标是开发针对肾病综合征高脂血症的特定机制治疗。职业发展计划已由申请人，主要导师和两位共同导师制定，以提供脂质生物学，蛋白质组学技术，细胞信号传导，沟通和演讲技巧，赠款和手稿写作以及负责任的研究行为的新的和增强的培训。在补助金发放的最后几年，共同导师的独立性和参与程度逐渐提高。每个具体目标的时间表，独立实验室空间的分配，申请人与指导委员会的定期会议，申请人的期望以及每个导师的具体角色都在职业发展计划中详细说明。此外，申请人预计将在前几年编写较小的基金会赠款，并在K奖的最后两年编写R 01申请。PI目前正在进行的研究工作已经揭示了血管生成素样-4（Angptl 4）在原发性肾小球疾病（如微小病变疾病）中肾病综合征的发展中的重要作用。Angptl 4是一种分泌的糖蛋白，其是脂蛋白脂肪酶的已知抑制剂，并且该蛋白质的血浆水平增加导致高脂血症（高脂血症的一种组分）的发展。PI进行的研究表明，足细胞分泌该蛋白的增加导致蛋白尿的发生（Clement LC Nature Medicine 2011）。在该提案中，申请人将研究糖皮质激素对足细胞中Angptl 4基因表达的调节，并研究肾病综合征中由足细胞分泌Angptl 4进入循环导致的高血糖症的发展。假设：微小病变疾病中足细胞Angptl 4表达的上调通过糖皮质激素治疗而减少，并且通过糖皮质激素受体与Angptl 4启动子中的负性糖皮质激素应答元件的结合而介导。在原发性肾小球疾病中，足细胞分泌的Angptl 4的唾液酸化影响其渗漏到循环中、抑制脂蛋白脂肪酶活性并产生高脂血症的能力。循环Angptl 4在HDL的表面上转运并直接抑制内皮结合的脂蛋白脂肪酶，并且通过其与载脂蛋白C-II和C-III的相互作用抑制内皮结合的脂蛋白脂肪酶。在具体目标1中，将研究糖皮质激素对Angptl 4启动子活性的调节。在具体目标2中，将研究唾液酸化和其他形式的翻译后修饰对足细胞分泌的Angptl 4渗漏到循环中以及由此产生的高胆红素血症的发展的影响。在 具体目的3，将研究Angptl 4与HDL表面上的载脂蛋白C-II（脂蛋白脂酶的激活剂）和C-III（脂蛋白脂酶的抑制剂）的推定相互作用。

DESCRIPTION (provided by applicant): Nephrotic syndrome is a major cause of kidney failure, and patients with this condition develop large amounts of proteinuria and elevated levels of plasma lipids (triglycerides and cholesterol). The immediate goal of the PI / applicant is to study in detail the mechanisms behind the development of hypertriglyceridemia in nephrotic syndrome. The PI's long term goal is to develop specific mechanism-based therapy for hyperlipidemia in nephrotic syndrome. The career development plan has been developed by the applicant, the primary mentor, and the two co-mentors to provide new and enhanced training in lipid biology, proteomic techniques, cell signaling, communication and presentation skills, grant and manuscript writing, and responsible conduct of research. There is a progressive increase in independence and greater involvement of the co-mentors in the later years of the grant. Timelines for each Specific Aim, allocation of independent laboratory space, periodic meetings of the applicant with the mentoring committee, expectations from the applicant and the specific role of each mentor are addressed in detail in the career development plan. In addition, the applicant is expected to write smaller foundation grants in the earlier years, and a R01 application in the last two years of the K Award. Research work currently being conducted by the PI has revealed an important role of Angiopoietin-like-4 (Angptl4) in the development of nephrotic syndrome in primary glomerular diseases like minimal change disease. Angptl4 is a secreted glycoprotein that is a known inhibitor of lipoprotein lipase and increased plasma levels of this protein result in the development of hypertriglyceridemia (a component of hyperlipidemia). Studies conducted by the PI reveal that increased secretion of this protein from the podocyte results in the development of proteinuria (Clement LC Nature Medicine 2011). In this proposal, the applicant will study the regulation of Angptl4 gene expression in the podocyte by glucocorticoids, and investigate the development of hypertriglyceridemia resulting from podocyte secretion of Angptl4 into the circulation in nephrotic syndrome. Hypothesis: The upregulation of podocyte Angptl4 expression in minimal change disease is reduced by treatment with glucocorticoids, and is mediated via binding of the glucocorticoid receptor to a negative glucocorticoid response element in the Angptl4 promoter. In primary glomerular disease, the sialylation of podocyte secreted Angptl4 influences its ability to leak into the circulation, inhibt lipoprotein lipase activity, and produce hypertriglyceridemia. Circulating Angptl4 is transported on the surface of HDL and inhibits endothelium bound lipoprotein lipase directly, and via its interaction with apolipoproteins C-II and C-III. In Specific Aim 1, the regulation of the Angptl4 promoter activity by glucocorticoids will be studied. In Specific Aim 2, the influence of sialylatin and other forms of posttranslational modification in the leakage of podocyte secreted Angptl4 into the circulation and the resulting development of hypertriglyceridemia will be investigated. In Specific Aim 3, putative interactions of Angptl4 with apolipoproteins C-II (activator of lipoprotei lipase) and C-III, (inhibitor of lipoprotein lipase) on the surface of HDL will be studied.