DHDDS and Retinal Degeneration

DHDDS 和视网膜变性

基本信息

批准号：
8850445
负责人：
RONG WEN
金额：
$ 56.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850445
关键词：
Accounting Affect Anabolism Ashkenazim Binding Biochemical Biological Markers Biological Process Blindness Blood Clinical Degenerative Disorder Diagnostic Diphosphates Disease Dolichol Enzymes Fibroblasts Genes Goals Health Human Hydroxymethylglutaryl-CoA reductase Individual Inherited Knock-in Mouse Knowledge Lead Length Link Measures Membrane Membrane Protein Traffic Metabolism Molecular Morphogenesis Mus Mutant Strains Mice Mutation Natural History Pathogenesis Patients Phenotype Photoreceptors Physiological Plasma Play Population Process Research Retinal Degeneration Retinitis Pigmentosa Rhodopsin Role Sampling Skin Squalene Synthetase Structure Synaptic Transmission System Testing Urine Vesicle Work base cell type disease diagnosis disease natural history effective therapy follower of religion Jewish glycosylation insight mouse model mutation carrier novel photoreceptor degeneration treatment strategy urinary

项目摘要

DESCRIPTION (provided by applicant): Retinal degeneration is a major cause of blindness, yet no effective treatments are available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa (RP), a group of inherited retinal degenerative disorders. We recently identified a novel RP-causing mutation in the gene that encodes DHDDS (dehydrodolichol diphosphate synthase), a key enzyme of dolichol biosynthesis. A single base c.124A>G mutation changes the highly conserved Lys42 in DHDDS to a Glu residue, resulting in weak substrate binding and lowered catalytic efficiency. This mutation accounts for 12% of all the autosomal recessive RP cases in Ashkenazi Jewish (AJ) patients and is heterozygous in 1 in 322 in the AJ population. A large knowledge gap exists in our understanding of the link between the DHDDS mutation and retinal degeneration. For example, the exact biological functions of free dolichols, the final products of DHDDS, are not well understood. This mutation provides a rare opportunity to study the roles of free dolichols in photoreceptors. In addition, th molecular and clinical insights obtained from our studies will help to develop novel therapies. Two Hypotheses are proposed: 1) The K42E DHDDS mutation alters dolichol profile and causes dolichol deficiency in photoreceptors, leading to retinal degeneration; 2) Free dolichols play essential roles in the structure and functions of photoreceptors, including membrane trafficking and vesicle fusion, which is vitally important in outer segment (OS) morphogenesis, renewal, and synaptic transmission. We also propose 3 Specific Aims to test these hypotheses: 1) Study the effect s of DHDDS mutations on dolichol metabolism in human ; 2) Study the mechanism of retinal degeneration caused by the DHDDS mutation in mouse ; 3) Study the biological functions of free dolichols in photoreceptors. We will study dolichol metabolism in fibroblasts, as well as blood and urine from patients. We will also use a mouse model that harbors the K42E DHDDS mutation to understand retinal degeneration caused by dolichol deficiency, and the structural and functional roles of dolichols in photoreceptors. Through the proposed work, we will gain an understanding of the disease process and mechanism caused by DHDDS mutations, and the functions of free dolichols in photoreceptors, with the ultimate goal of developing novel and effective therapies.

描述（申请人提供）：视网膜变性是失明的主要原因，但目前尚无有效的治疗方法。据估计，每 3,500 至 4,000 人中就有一人患有色素性视网膜炎 (RP)，这是一组遗传性视网膜退行性疾病。我们最近在编码 DHDDS（脱氢多羟基化合物二磷酸合酶）的基因中发现了一种新的 RP 引起突变，DHDDS 是多羟基化合物生物合成的关键酶。单碱基c.124A>G突变将DHDDS中高度保守的Lys42改变为Glu残基，导致底物结合弱并降低催化效率。这种突变占德系犹太人 (AJ) 患者所有常染色体隐性 RP 病例的 12%，并且在 AJ 人群中，每 322 人中有 1 人是杂合的。我们对 DHDDS 突变与视网膜变性之间的联系的理解存在很大的知识差距。例如，DHDDS 的最终产物游离多羟基化合物的确切生物学功能尚不清楚。这种突变为研究游离多羟基化合物在光感受器中的作用提供了难得的机会。此外，从我们的研究中获得的分子和临床见解将有助于开发新的疗法。提出了两个假设：1）K42E DHDDS 突变改变了多醇谱并导致光感受器中多醇缺乏，导致视网膜变性； 2）游离多醇在光感受器的结构和功能中发挥重要作用，包括膜运输和囊泡融合，这对于外节（OS）形态发生、更新和突触传递至关重要。我们还提出了 3 个具体目标来检验这些假设：1）研究 DHDDS 突变对人类多醇代谢的影响； 2）研究DHDDS突变引起小鼠视网膜变性的机制； 3）研究游离多羟基化合物在光感受器中的生物学功能。我们将研究成纤维细胞中的多萜醇代谢，如以及患者的血液和尿液。我们还将使用带有 K42E DHDDS 突变的小鼠模型来了解多醇缺乏引起的视网膜变性，以及多醇在光感受器中的结构和功能作用。通过这项工作，我们将了解DHDDS突变引起的疾病过程和机制，以及光感受器中游离多羟基化合物的功能，最终目标是开发新颖有效的疗法。