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: 8293560
• 负责人: Bo Chen
• 金额: $ 41.48万
• 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/8293560
• 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; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We propose to utilize the pro-survival effect of HDAC4 (histone deacetylase 4) to protect retinal neurons in retinal degenerative diseases that cause progressive vision loss in humans. Understanding the mechanisms by which HDAD4 functions in the retina may lead to new therapeutic interventions for other degenerative diseases in the central nervous system, such as Alzheimer's disease, Huntington's disease, and spinocerebellar ataxia.

描述（由申请人提供）：美国失明的主要原因是视网膜变性，通常涉及光感受器（杆和锥体）的死亡。色素性视网膜炎（RP）是指通常由杆特异性基因突变引起的主要遗传性视网膜退行性疾病。这些遗传缺陷导致杆死亡，然后逐渐变性正常锥。锥死导致RP逐渐视力丧失。 RP在美国影响100,000多人，目前没有治疗或预防。我们的长期目标是了解RP中光感受器变性的机制，并开发可节省感光体并恢复RP患者的视觉功能的疗法。拯救棒的主要挑战是RP的异质性质，因为在杆特异性基因中已经确定了许多突变。因此，每个突变可能需要独特的疗法。相比之下，储蓄锥可以提供更一般的手段来保存RP的愿景。我们先前的研究表明，HDAC4在RP小鼠模型中促进杆存活中的新作用。我们将通过以下目的扩大研究：目标1）我们将研究HDAC4通过该机制保护视网膜变性小鼠中的感光体的分子和细胞机制。使用CRE-LOXP系统限制了特定细胞类型中的HDAC4表达，我们将通过细胞自主机制与其他细胞类型中的HDAC4效应来测试HDAC4是否在光感受器中发挥其促生存效应。我们将进一步测试HDAC4脱乙酰基酶结构域是否需要其在光感受器保护中的作用。 AIM 2）我们将测试HDAC4是否可以在快速和较慢的视网膜变性模型中保存感光体。使用AAV（腺相关病毒）在RD1小鼠中介导的基因转移（快速视网膜变性模型），我们将测试HDAC4是否直接促进锥体存活。我们将测试锥光转导的锥体结构和关键成分。使用AAV介导的基因转移在VPP和RD10小鼠中（视网膜变性模型较慢），我们将研究1）光感受器保护是否需要HDAC4的发育表达； 2）HDAC4是否可以用作受感受器保护的更一般的生存因子。目标3）我们将研究视网膜变性过程中灭活并在HDAC4储存的锥中重新激活的主要生存信号通路。我们将进一步测试HDAC4储物锥是否恢复视觉功能：1）电生理学测试视网膜和视觉皮层中神经回路的完整性； 2）确定救出的视网膜功能是否可以指导复杂行为的行为测试。总而言之，我们提出的研究将阐明HDAC4促进感光体的存活的分子和细胞机制和途径，这是视网膜遗传疾病的主要靶标。我们提出的关于HDAC4在杆和锥体中的亲卵巢效应的研究将推进针对主要的盲目疾病的治疗范式。 公共卫生相关性：我们建议利用HDAC4（组蛋白脱乙酰基酶4）的促生物生存作用来保护视网膜退行性疾病中导致人类渐进视力丧失的视网膜神经元。了解HDAD4在视网膜中起作用的机制可能会导致中枢神经系统中其他退行性疾病的新治疗干预措施，例如阿尔茨海默氏病，亨廷顿氏病和脊椎小脑共济失调。