Molecular Pathobiology of Alport Syndrome

Col4A3、Col4A4和Col4A5基因的数百个变异导致广泛的 肾小球疾病对肾小球基底膜功能的影响 患有阿尔波特综合征。这些基因编码IV型胶原α345支架的组装， GBM的组成部分。这些致病变种导致了一系列广泛的临床表现， 范围从镜下血尿到终末期肾病。潜在的机制 将这些变异与基底膜异常和肾功能衰竭联系起来仍不清楚。现代疗法 仅限于用血管紧张素转换酶抑制剂来延缓病情进展，新的治疗方法迫在眉睫 需要。 目前尚不清楚α支架的遗传变异是如何导致阿尔波特综合征的。在这里，我们 关注导致阿尔波特综合征的Z-变异，而不是丢失α345支架，而是减少- 或功能丧失效应(低形态变异)。我们用这个变体作为先锋来破译 α345 IV型胶原在Alport GBM中的致病机制及开发新的治疗方法。 在目标1中，我们将利用一种新的Z变异动物模型来了解α345胶原蛋白的作用机制 静脉功能障碍。在目标2中，我们将确定Z变量和类似变量所造成的确切缺陷 蛋白质和细胞水平的致病变异体识别小分子的特定靶点 治疗。在目标3中，我们将测试蛋白质替代疗法并筛选药理作用 伴侣纠正了IV型胶原α345支架的组装和稳定性。 这些目标的完成将促进我们对Alport发病机制的了解，并为 为解决Alport综合征的致病机制的治疗开发奠定基础。

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.