Pharmacotherapy for Retinal Degenerative Disorders

视网膜退行性疾病的药物治疗

• 批准号: 9110900
• 负责人: RALPH J. JENSEN
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110900
• 关键词: Accounting; Affect; Age related macular degeneration; Animal Model; Blindness; Cells; Degenerative Disorder; Goals; Health; Implant; In Vitro; Legal Blindness; Light; Modeling; Mus; Neurons; Neurotransmitter Receptor; Output; Patients; Pharmacotherapy; Photophobia; Photoreceptors; Preparation; Presynaptic Terminals; Property; Rattus; Reporting; Research Personnel; Residual state; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Retinitis Pigmentosa; Signal Transduction; Stem cells; Stimulus; Synaptic Receptors; System; Therapeutic; Vision; Visual; Visual Perception; Work; follow-up; gamma-Aminobutyric Acid; gene therapy; improved; metabotropic glutamate receptor type 1; multi-electrode arrays; novel strategies; optogenetics; photoreceptor degeneration; presynaptic; receptive field; receptor; response; retinal prosthesis; transmission process; visual stimulus

DESCRIPTION (provided by applicant): Restoring vision loss in patients with retinal degenerative disorders, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RD) is a goal of many researchers, who are using different therapeutic strategies, including retinal prosthetic implants, optogenetics, stem cell treatments, and gene therapy. A novel approach is the use of a pharmacological agent that acts on synaptic receptors to facilitate transmission of residual, visual signals in the degenerate retina. This approach has not been considered previously. However, recently I discovered that when a GABAc receptor antagonist (TPMPA) is applied to the retina of a P23H rat (model of retinitis pigmentosa), retinal ganglion cells (RGCs) became more sensitive to a light stimulus. The working hypothesis is that there is an increase in tonic inhibition at the axon terminals of bipolar cells in the degenerate retina, and this increased inhibition impedes transmission of photoreceptor signals to RGCs. An alternative to blocking GABAergic receptors on axon terminals of bipolar cells is to block the release of GABA onto the terminals. The metabotropic glutamate type 1 (mGlu1) receptor is reported to modulate GABA release onto bipolar cell axon terminals. I found that the mGlu1 receptor antagonist JNJ16259685 also increased light sensitivity of RGCs in the P23H rat retina. In the proposed study, I plan to follow up on these observations by further evaluating the effects of these receptor antagonists on the receptive field properties of P23H rat RGCs, and to validate these findings in another animal model of retinal degeneration. There are three specific aims in this proposed project. Each specific aim will entail the recording of light responses from RGCs with multielectrode arrays. Aim 1 will examine the effects of blocking GABAc receptors on the receptive field properties of P23H rat RGCs, and Aim 2 will examine the effects of blocking mGlu1 receptors. Aim 3 will determine whether the effects of the GABAc and mGlu1 receptor blockers are reproducible in another model of retinal degeneration (the rd10 mouse). The findings will provide important information on how these neurotransmitter receptor antagonists may alter visual perception in patients with retinal degeneration.

描述（由申请人提供）： 恢复视网膜退行性疾病患者的视力丧失，例如年龄相关的黄斑变性（AMD）和色素性视网膜炎（RD）是许多研究人员的目标，他们使用了不同的治疗策略，包括视网膜假体植入植入物，光遗传学，干细胞治疗和基因治疗。一种新颖的方法是使用作用于突触受体的药理学剂来促进退化视网膜中残留的视觉信号的传播。以前尚未考虑这种方法。但是，最近我发现，当GABAC受体拮抗剂（TPMPA）应用于P23H大鼠的视网膜（色素性视网膜炎模型）时，视网膜神经节细胞（RGC）对光刺激变得更加敏感。工作假设是轴突的强直抑制作用增加 退化视网膜中双极细胞的末端，这种增加的抑制作用阻碍了光感受器信号向RGC的传播。在双极细胞的轴突末端阻断GABA能受体的一种替代方法是阻止GABA释放到末端。据报道，代谢型谷氨酸1型（MGLU1）受体可将GABA释放到双极细胞轴突末端。我发现MGLU1受体拮抗剂JNJ16259685还提高了P23H大鼠视网膜中RGC的光敏度。在拟议的研究中，我计划遵循 通过进一步评估这些受体拮抗剂对p23H大鼠RGC的接受场特性的影响，并在另一种视网膜变性动物模型中验证这些发现，从而提高这些观察结果。这个拟议的项目有三个特定的目标。每个特定的目标都需要用多电极阵列记录来自RGC的光响应。 AIM 1将检查阻断GABAC受体对P23H大鼠RGC的接受场特性的影响，AIM 2将检查阻断MGLU1受体的影响。 AIM 3将确定在另一种视网膜变性模型（RD10小鼠）中，GABAC和MGLU1受体阻滞剂的影响是否可再现。这些发现将提供有关这些神经递质受体拮抗剂如何改变视网膜变性患者的视觉感知的重要信息。