Investigation of Nephrotic Syndrome

肾病综合症的调查

• 批准号: 8352811
• 负责人: Lionel Claudius Clement
• 金额: $ 15.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352811
• 关键词: Address; Adipose tissue; Affect; Angiopoietins; Basement membrane; Binding; Binding Proteins; Biological; Biology; Blood Circulation; Charge; Cholesterol; Complex; Data; Development; Development Plans; Diffuse; Disease; Edema; Endothelium; Event; Extravasation; Foot Process; Foundations; Gene Expression; Genes; Glucocorticoid Receptor; Glucocorticoids; Glycoproteins; Goals; Grant; High Density Lipoproteins; Hour; Human; Hyperlipidemia; Hypertriglyceridemia; Hypoalbuminemia; In Vitro; Investigation; K-Series Research Career Programs; Kidney Failure; Laboratories; Link; Lipase; Lipids; Lipoprotein Binding; Manuscripts; Mediating; Mediator of activation protein; Medicine; Mentors; Mus; Nature; Nephrosis; Nephrotic Syndrome; Organ; Pathogenesis; Patients; Plasma; Post-Translational Protein Processing; Protein Secretion; Proteins; Proteinuria; Proteomics; Publishing; Puromycin; Rattus; Recombinant Proteins; Regulation; Relative (related person); Renal glomerular disease; Reporter; Research; Response Elements; Role; Sialic Acids; Signal Transduction; Staging; Surface; Techniques; TimeLine; Tissues; Training; Transgenic Organisms; Triglycerides; Up-Regulation; Vascular Endothelium; Work; Writing; apolipoprotein C-II; base; career development; expectation; glomerular basement membrane; hypercholesterolemia; improved; lipoprotein lipase; lipoprotein lipase inhibitor; meetings; particle; podocyte; promoter; receptor; responsible research conduct; sialylation; skills; study characteristics; uptake

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. PUBLIC HEALTH RELEVANCE: This proposal will investigate the biological role of podocyte-secreted Angiopoietin-like-4 in the pathogenesis of hypertriglyceridemia in 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水平升高（甘油三酸酯和胆固醇）。 PI /申请人的直接目标是详细研究肾病综合征中高甘油三酸酯血症的机制。 PI的长期目标是开发基于肾病综合征高脂血症的特定机制治疗。职业发展计划是由申请人，主要导师和两位副主管制定的，以提供脂质生物学，蛋白质组学技术，细胞信号，沟通和表现能力，赠款和手稿写作以及负责任的研究的新培训。在赠款的后期，独立性逐渐增加，并更大的参与者参与。在职业发展计划中详细介绍了每个特定目标的时间表，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特定作用。此外，预计申请人将在早期撰写较小的基金会赠款，并在K奖的最后两年中提供R01申请。 PI目前正在进行的研究工作揭示了类似血管素的4（Angptl4）在原发性肾小球疾病（如最小变化疾病）中的肾病综合征发展中的重要作用。 ANGPTL4是一种分泌的糖蛋白，是一种已知的脂蛋白脂肪酶抑制剂，该蛋白质的血浆水平升高会导致高甘油三酯血症的发展（高脂血症的成分）。 PI进行的研究表明，该蛋白质从足细胞中分泌增加会导致蛋白尿的发展（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ANGPTL4基因表达的调节，并研究由Angptl4足细胞分泌到肾病综合征中的循环中的高糖节性血症。假设：用糖皮质激素治疗减少了在最小变化疾病中足细胞ANGPTL4表达的上调，并通过糖皮质激素受体与ANGPTL4启动子中糖皮质激素反应元件的结合介导。在原发性肾小球疾病中，足细胞分泌的ANGPTL4的溶作会影响其渗入循环，抑制脂蛋白脂肪酶活性并产生高甘油三酸酯血症的能力。循环ANGPTL4在HDL表面转运，并直接抑制内皮结合的脂蛋白脂肪酶，并通过与载脂蛋白C-II和C-III的相互作用。在特定的目标1中，将研究糖皮质激素对ANGPTL4启动子活性的调节。在特定的目标2中，将研究乙兰氨扬林和其他形式的翻译后修饰在循环中分泌的Angptl4泄漏中的影响，并研究由此产生的高甘油三酸酯血症的发展。在 特定目标3，ANGPTL4与载脂蛋白C-II（脂蛋白脂肪酶的激活剂）和C-III（脂蛋白脂肪酶抑制剂）在HDL表面上的推定相互作用。 公共卫生相关性：该提案将研究足细胞分泌的类似血管素的样子在肾病综合征中高甘油三酸酯血症发病机理中的生物学作用。