UNDERSTANDING THE ROLE OF RETINOL DEHYDROGENASES RDH11 AND RDH12 IN VISION

了解视黄醇脱氢酶 RDH11 和 RDH12 在视觉中的作用

• 批准号: 7720540
• 负责人: Anne Kasus-Jacobi
• 金额: $ 21.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720540
• 关键词: 4 hydroxynonenal; Apoptosis; Blindness; Cell physiology; Clinical; Computer Retrieval of Information on Scientific Projects Database; Cultured Cells; Disease; Enzymes; Funding; Genes; Grant; In Vitro; Inherited; Institution; Leber' s amaurosis; Light; Lipid Peroxidation; Mus; Mutation; Oxidative Stress; Patients; Photoreceptors; Physiological; Proteins; Research; Research Personnel; Resources; Retina; Retinal Dystrophy; Retinol dehydrogenase; Role; Source; Testing; United States National Institutes of Health; Vision; adduct; in vivo

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The retinol dehydrogenase RDH12 was identified as a disease-causing gene for Leber Congenital Amaurosis, the earliest and most severe inherited retinal dystrophy. The physiological role of RDH12 is unknown. We hypothesize that RDH12 inactivates toxic molecules produced during oxidative stress in photoreceptors. We also hypothesize that the closely related enzyme, RDH11, has the same function. Bright light induces oxidative stress and lipid peroxidation in photoreceptors, leading to the formation of toxic 4-hydroxynonenal (4-HNE). 4-HNE forms adduct with proteins disrupting important cellular functions. Adducts accumulate in photoreceptors during bright light exposure prior to photoreceptor apoptosis. RDH11 and RDH12 were shown to reduce 4-HNE in vitro and we found evidences that they protect cultured cells and photoreceptors against 4-HNE-induced adduct formation and apoptosis. The following specific aims will allow us to further test our hypothesis. Aim 1: Characterize the catalytic activities of RDH11 and RDH12 towards 4-HNE in vitro and in mouse retina. Aim 2: Determine whether RDH11 and RDH12 are protective against the formation of 4-HNE-protein adducts and apoptosis of photoreceptors in vivo. Aim 3: Test the hypothesis that RDH11 compensates for RDH12 in the mouse retina. If we successfully demonstrate that the physiological role of RDH11 and RDH12 is to detoxify 4-HNE in photoreceptor inner segments, this will have a clinical impact because it will provide a strategy for the treatment of patients with a progressive loss of vision due to RDH12 mutations.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 视黄醇脱氢酶 RDH12 被确定为莱伯先天性黑蒙（最早也是最严重的遗传性视网膜营养不良）的致病基因。 RDH12 的生理作用尚不清楚。我们假设 RDH12 可以使光感受器氧化应激过程中产生的有毒分子失活。我们还假设密切相关的酶 RDH11 具有相同的功能。亮光会诱导光感受器中的氧化应激和脂质过氧化，导致有毒的 4-羟基壬烯醛 (4-HNE) 的形成。 4-HNE 与蛋白质形成加合物，破坏重要的细胞功能。在光感受器凋亡之前，在强光照射期间，加合物在光感受器中积累。 RDH11 和 RDH12 在体外被证明可以减少 4-HNE，我们发现有证据表明它们可以保护培养细胞和光感受器免受 4-HNE 诱导的加合物形成和细胞凋亡。 以下具体目标将使我们能够进一步检验我们的假设。目标 1：在体外和小鼠视网膜中表征 RDH11 和 RDH12 对 4-HNE 的催化活性。目标 2：确定 RDH11 和 RDH12 是否具有保护作用，防止体内 4-HNE-蛋白加合物的形成和光感受器细胞凋亡。目标 3：检验 RDH11 在小鼠视网膜中补偿 RDH12 的假设。如果我们成功证明 RDH11 和 RDH12 的生理作用是对光感受器内节中的 4-HNE 进行解毒，这将产生临床影响，因为它将为治疗因 RDH12 突变而导致视力进行性丧失的患者提供策略。