UBIAD1基因突变导致施耐德角膜营养不良症的分子机制

施耐德角膜营养不良症（SCD）是一种罕见的角膜疾病，表现为在角膜中出现大量胆固醇的异常堆积，引起角膜混浊，导致视力下降。最近在SCD病人中发现许多UBIAD1基因的点突变，然而UBIAD1蛋白如何调控胆固醇代谢，目前尚不清楚。前期我们通过串联亲和纯化-质谱，鉴定出UBIAD1能结合胆固醇合成途径中的关键限速酶HMGCR。初步发现UBIAD1发生SCD相关的突变后滞留在内质网，显著地抑制HMGCR的降解。本项目将在此基础上，进一步深入研究UBIAD1调控HMGCR降解的分子机制。同时我们获得了UBIAD1 SCD相关点突变的knock-in小鼠，在此基础上进一步分析小鼠角膜的组织病理学表型，建立SCD的疾病模型，并探索治疗SCD的方法。本项目旨在揭示UBIAD1调控HMGCR降解的分子机制，和突变后导致角膜中胆固醇堆积的致病机理，以期为SCD的治疗和新型降胆固醇药物的研发提供新的思路。

Schnyder corneal dystrophy (SCD) is an unusual cornea disease, characterized by progressive opacification of cornea resulting from abnormal deposition of cholesterol within the cornea, which lead to decrease of vision. Recently many point mutations in UBIAD1 gene were found in SCD patients; however, it is still unknown how UBIAD1 regulate cholesterol metabolism. In the preliminary studies, by the method of tandem affinity purification-mass spectrometry, we identified that UBIAD1 can interact with HMGCR, the key rate limiting enzyme of cholesterol synthesis. The SCD-associated UBIAD1 mutants remain sequestered in ER membranes, and prevent the degradation of HMGCR. In this proposal, we will further investigate the molecular mechanism of UBIAD1 regulating the degradation of HMGCR. Meanwhile, we constructed the knock-in mice with SCD-related mutation of UBIAD1. We will further investigate the histopathological phenotype of UBIAD1 mutant mice in the cornea; establish the disease model of SCD and explore the way to treat SCD. This proposal aims to elucidate the molecular mechanism of UBIAD1 modulating the degradation of HMGCR, and the pathogenesis of mutated UBIAD1 causing abnormal deposition of cholesterol within cornea. We expect that this project will provide clues for the developing new therapies to prevent SCD, and for the developing new types of cholesterol lowering drugs.