HDAC4-mediated Photoreceptor Protection in Retinal Degeneration

HDAC4 介导的视网膜变性中的光感受器保护

• 批准号: 8457117
• 负责人: Bo Chen
• 金额: $ 39.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457117
• 关键词: Affect; Alzheimer' s Disease; Behavior; Biological Assay; Blindness; Bone Development; C-terminal; Cells; Central Nervous System Degenerative Diseases; Cessation of life; Complex; Deacetylase; Degenerative Disorder; Dependovirus; Development; Disease; Electrophysiology (science); Gene Mutation; Gene Transfer; Genes; Goals; Hereditary Disease; Human; Huntington Disease; Inherited; Lead; Mediating; Modeling; Molecular; Mus; Muscle Development; Mutation; N-terminal; Nature; Neuraxis; Pathway interactions; Patients; Photoreceptors; Phototransduction; Play; Prevention; Research; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Role; Signal Pathway; Signal Transduction; Spinocerebellar Ataxias; Structure; System; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Studies; United States; Vertebrate Photoreceptors; Vision; Visual; Visual Cortex; abstracting; behavior test; cell type; human HDAC4 protein; mouse model; neural circuit; neuronal survival; novel; novel therapeutic intervention; photoreceptor degeneration; prevent; restoration; retinal neuron; retinal rods; therapy development

Project Summary/Abstract: The leading cause of blindness in the United States is retinal degeneration, typically involving the death of photoreceptors (rods and cones). Retinitis pigmentosa (RP) refers to a major group of hereditary retinal degenerative diseases commonly caused by mutations in rod-specific genes. These genetic defects cause rods to die followed by gradual degeneration of normal cones. It is cone death that results in progressive vision loss in RP. RP affects over 100,000 people in the United States with no treatment or prevention currently available. Our long-term goal is to understand the mechanism of photoreceptor degeneration in RP and to develop therapies that save photoreceptors and restore visual function in RP patients. A major challenge to saving rods is the heterogeneous nature of RP, as many mutations have been identified in rod-specific genes; thus, each mutation may require a unique therapy. By contrast, saving cones may provide a more general means to save vision for RP. Our previous study demonstrated a novel role of HDAC4 in promoting rod survival in a mouse model of RP. We will expand our studies through the following Aims: Aim 1) we will investigate the molecular and cellular mechanisms through which HDAC4 protects photoreceptors in retinal degeneration mice. Using a cre-loxp system to restrict HDAC4 expression in specific cell types, we will test whether HDAC4 exerts its pro-survival effect in photoreceptors through a cell-autonomous mechanism versus HDAC4's effect in other cell types. We will further test whether the HDAC4 deacetylase domain is required for its effect in photoreceptor protection. Aim 2) we will test whether HDAC4 saves photoreceptors in both fast and slower retinal degeneration models. Using AAV(adeno-associated virus)-mediated gene transfer in rd1 mice (a fast retinal degeneration model), we will test whether HDAC4 directly promotes cone survival. We will test for preserved cone structure and critical components in cone phototransduction. Using AAV-mediated gene transfer in VPP and rd10 mice (slower retinal degeneration models), we will investigate 1) whether photoreceptor protection requires developmental expression of HDAC4; 2) whether HDAC4 can be used as a more general survival factor for photoreceptor protection. Aim 3) we will investigate major survival signaling pathways that are inactivated during retinal degeneration and reactivated in HDAC4-saved cones. We will further test whether HDAC4-saved cones restore visual function using: 1) electrophysiology to test the integrity of neural circuits in the retina and visual cortex; 2) behavioral tests to determine whether rescued retinal function can guide complex behaviors. In summary, our proposed studies will elucidate the molecular and cellular mechanisms and pathways through which HDAC4 promotes the survival of photoreceptors, the main target of genetic diseases in the retina. Our proposed research on the pro-survival effect of HDAC4 in both rods and cones will advance the therapeutic paradigm for a major group of blinding diseases.

项目摘要/摘要： 在美国，导致失明的主要原因是视网膜变性，通常会导致死亡 感光细胞（视杆细胞和视锥细胞）。视网膜色素变性（RP）是指一大类遗传性视网膜疾病 通常由视杆细胞特异性基因突变引起的退行性疾病。这些基因缺陷导致 视杆细胞死亡，随后正常视锥细胞逐渐退化。视锥细胞死亡导致视力进步 RP 损失。美国有超过 100,000 人患有 RP，目前尚无治疗或预防措施 可用的。我们的长期目标是了解 RP 中光感受器变性的机制并 开发拯救 RP 患者光感受器并恢复视觉功能的疗法。一个重大挑战 保存视杆细胞是 RP 的异质性，因为在视杆细胞特异性基因中已发现许多突变； 因此，每种突变可能需要独特的治疗。相比之下，保存锥体可以提供更通用的方法 意思是为RP保存视力。我们之前的研究证明了 HDAC4 在促进视杆细胞中的新作用 RP 小鼠模型中的存活率。我们将通过以下目标扩展我们的研究： 目标 1) 我们将 研究 HDAC4 保护视网膜光感受器的分子和细胞机制 退化小鼠。使用 cre-loxp 系统限制特定细胞类型中的 HDAC4 表达，我们将测试 HDAC4 是否通过细胞自主机制与光感受器发挥其促生存作用 HDAC4 对其他细胞类型的影响。我们将进一步测试HDAC4脱乙酰酶结构域是否是必需的 其对光感受器保护的作用。目标 2）我们将测试 HDAC4 是否能以快速和快速的方式保存光感受器 较慢的视网膜变性模型。在 rd1 小鼠中使用 AAV（腺相关病毒）介导的基因转移（a 快速视网膜变性模型），我们将测试 HDAC4 是否直接促进视锥细胞存活。我们将测试 保留锥体结构和锥体光转导中的关键成分。使用 AAV 介导的基因 在 VPP 和 rd10 小鼠（较慢的视网膜变性模型）中转移，我们将研究 1) 是否 光感受器保护需要 HDAC4 的发育表达； 2）HDAC4是否可以用作 用于光感受器保护的更一般的生存因子。目标 3）我们将研究主要的生存信号 在视网膜变性期间失活并在 HDAC4 保存的视锥细胞中重新激活的通路。我们将 使用以下方法进一步测试 HDAC4 保存的视锥细胞是否恢复视觉功能：1) 电生理学测试完整性 视网膜和视觉皮层的神经回路； 2）行为测试以确定是否挽救视网膜 功能可以指导复杂的行为。总之，我们提出的研究将阐明分子和 HDAC4 促进光感受器存活的细胞机制和途径， 视网膜遗传疾病的目标。我们提出的关于 HDAC4 在两种疾病中的促生存作用的研究 视杆细胞和视锥细胞将推进一大类致盲疾病的治疗模式。