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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：
10705147
负责人：
Sergey Petrovich Budko
金额：
$ 54.22万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705147
关键词：
Achievement Address 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 Individual Investigation Kidney Failure Knowledge Lead Link Microscopic Molecular Molecular Chaperones Morphology Mus Outcome Pathogenesis Pathogenicity Patients Precision therapeutics Prognosis Proteins Receptor Cell Residual state Site Structure Testing Translating Ultrafiltration Variant appendage collagen scaffold 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 pharmacologic scaffold 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 pathogenic mechanism of the α345 collagen IV in Alport GBM and develop new forms of therapy. In Aim 1, we will utilize a new Z-variant animal model to understand mechanisms of α345 collagen IV dysfunction. In Aim 2, we will determine exact 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 test protein replacement therapy and screen for pharmacological chaperones correcting 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 therapy development addressing causative mechanisms in Alport syndrome.

COL4A3、COL4A4和COL4A5基因中的数百种变体导致广泛的免疫缺陷。影响患者肾小球基底膜（GBM）功能的肾小球病 Alport综合征这些基因编码胶原IV α 345支架的组装，这是主要的 GBM的组成部分。致病变异导致广泛的临床表现，从显微镜下血尿到终末期肾病。潜在的机制将这些变异与GBM异常和肾衰竭联系起来仍然不清楚。当前治疗仅限于用ACE抑制剂治疗以减缓进展，迫切需要新的治疗方法需要的 α 345支架的遗传变异如何导致Alport综合征仍然未知。这里我们重点关注导致Alport综合征的Z变异体，而不损失α 345支架，而是减少- 或功能丧失效应（亚型变体）。我们用这个变体作为先锋来破译 Alport GBM中α 345胶原IV的致病机制，并开发新的治疗形式。在目的1中，我们将利用一种新的Z变异动物模型来了解α 345胶原的机制， IV功能障碍。在目标2中，我们将确定由Z变体和类似物引起的确切缺陷。在蛋白质和细胞水平上的致病性变体，以鉴定小分子的特异性靶标治疗在目标3中，我们将测试蛋白质替代疗法，并筛选药理学分子伴侣校正胶原IV α 345支架的组装和稳定性。目的的完成将推进我们对Alport发病机制的认识，为解决Alport综合征病因机制的治疗开发奠定了基础。