Molecular Pathobiology of Alport Syndrome

阿尔波特综合征的分子病理学

基本信息

批准号：
10476071
负责人：
Sergey Petrovich Budko
金额：
$ 10万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476071
关键词：
Achievement Adult Affect Angiotensin-Converting Enzyme Inhibitors Animal Model Architecture Binding Sites Biological COL4A3 gene Cells Chronic Kidney Failure Clinical Collagen Collagen Type IV Cysteine Defect Deposition Development Disease End stage renal failure Foundations Functional disorder Genes Genetic Genetic Variation Hematuria Hereditary nephritis In Vitro Individual Investigation Kidney Failure Knowledge Lead Link Microscopic Molecular Morphology Mus Pathogenesis Pathogenicity Patients Prognosis Proteins Receptor Cell Residual state Signal Transduction Site Structure Ultrafiltration Variant appendage base enzyme replacement therapy genetic variant glomerular basement membrane glomerular filtration glomerular function improved insight kindred loss of function mouse model novel therapeutic intervention novel therapeutics scaffold screening small molecule therapy development

项目摘要

Hundreds of variants in the COL4A3, COL4A4 and COL4A5 genes cause a broad range of glomerulopathies affecting the function of the glomerular basement membrane (GBM) in patients with Alport syndrome. These genes encode the assembly of collagen IV α345 scaffolds, the major constituent of the GBM. The pathogenic variants lead to a broad array of clinical manifestations, ranging from microscopic hematuria to end stage renal disease. The underlying mechanisms linking these variants with GBM abnormalities and renal failure remain obscure. Current therapy is limited to treatment with ACE inhibitors to slow progression and new therapies are in urgent need. How genetic variants of the α345 scaffold cause Alport syndrome remains unknown. Here, we focus on Z-variant causing Alport syndrome without loss of the α345 scaffold but rather reduction- or loss-of-function effect (hypomorph variant). We use this variant as a vanguard to decipher the function of the α345 collagen IV in GBM and develop new therapeutic approaches against Alport syndrome. In Aim 1, we will utilize new Z-variant animal models to understand mechanisms of α345 collagen IV function and dysfunction. In Aim 2, we will determine exact functional defects caused by Z-variant and similar pathogenic variants at protein and cellular levels to identify specific targets for small molecule therapies. In Aim 3, we will identify candidates for potential therapy by performing in vitro screening of natural and synthetic small molecules affecting assembly and stability of the collagen IV α345 scaffold. The completion of the Aims will advance our knowledge about Alport pathogenesis and lay out foundation for development of therapy against Alport syndrome.

COL4A3、COL4A4 和 COL4A5 基因中的数百个变异导致广泛的影响患者肾小球基底膜 (GBM) 功能的肾小球疾病这些基因编码 IV 型胶原 α345 支架的组装，这是主要的支架。 GBM 的致病变异导致广泛的临床表现，从镜下血尿到终末期肾病的潜在机制。目前的治疗方法仍不清楚这些变异与 GBM 异常和肾功能衰竭的关系。仅限于使用 ACE 抑制剂治疗来减缓进展，新疗法迫在眉睫需要。 α345 支架的遗传变异如何导致 Alport 综合征仍然未知。重点关注 Z 变体导致 Alport 综合征，但不损失 α345 支架，而是减少 - 或功能丧失效应（亚型变体）。我们使用该变体作为破译的先锋。 α345 IV 型胶原蛋白在 GBM 中的功能并开发针对 Alport 的新治疗方法在目标 1 中，我们将利用新的 Z 变体动物模型来了解该综合征的机制。 α345 IV 型胶原蛋白的功能和功能障碍在目标 2 中，我们将确定确切的功能缺陷。由Z变异和类似的蛋白质和细胞水平的致病变异引起，以识别在目标 3 中，我们将确定潜在的候选药物。通过对天然和合成小分子进行体外筛选来治疗 IV 型胶原 α345 支架的组装和稳定性。目标的完成将增进我们对 Alport 发病机制的了解，并奠定基础为开发针对阿尔波特综合征的疗法奠定了基础。