Retinal sheet transplant impact on functional organization of visual cortex in retinal degenerate animal models

视网膜片移植对视网膜退化动物模型视觉皮层功能组织的影响

• 批准号: 10612953
• 负责人: David C Lyon
• 金额: $ 58.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612953
• 关键词: 3-Dimensional; Address; Age; Age Months; Age related macular degeneration; Anatomy; Animal Model; Animals; Anterior; Area; Behavior; Blindness; Breeding; Cell Nucleus; Cells; Clinical; Collaborations; Complex; Conscious; Cues; Data; Disease; Dorsal; Electrocorticogram; Feedback; Frequencies; Generations; Goals; Histologic; Human; Image; Immunologic Deficiency Syndromes; Implant; Knowledge; Label; Lateral; Lead; Light; Maintenance; Medial; Methods; Microelectrodes; Midbrain structure; Modeling; Nerve; Neurons; Operative Surgical Procedures; Organoids; Outcome; Perforation; Persons; Photoreceptors; Play; Process; Rabies virus; Rattus; Recovery; Retina; Retinal Degeneration; Retinal Ganglion Cells; Retinitis Pigmentosa; Rodent; Rodent Model; Stream; Structure; Structure of retinal pigment epithelium; Surface; Surgeon; Synapses; Testing; Time; Tissue Donors; Tissues; Transgenic Organisms; Transplantation; Vision; Visual; Visual Cortex; Visual Pathways; Visual System; advanced disease; area striata; behavior test; blind; cell type; college; excitatory neuron; experimental study; extrastriate visual cortex; eye regeneration; fetal; flexibility; gene therapy; human embryonic stem cell; human tissue; image processing; improved; ineffective therapies; inhibitory neuron; neural circuit; neurophysiology; preference; progenitor; rabies viral tracing; remediation; response; retina transplantation; retinal progenitor cell; retinal regeneration; rho; sight restoration; skills; superior colliculus Corpora quadrigemina; visual information; visual processing

Millions of people worldwide suffer vision loss from progressed stages of age-related macular degeneration and retinitis pigmentosa. Through the disease, much of the retinal pigment epithelium (RPE) and many photoreceptors are irreversibly lost and new cutting edge treatments using trophic factors or gene therapy are ineffective because the tissues are no longer present to be rescued. Our goal is to remediate vision loss through transplantation of retinal progenitor tissue sheets into the degenerated retina. In rodent models of retinal degeneration (RD), several studies have demonstrated that retinal progenitor sheets successfully integrate into the host retina, through synaptic connectivity between the transplant retina and host, and evoke responses to flashes of light in the superior colliculus (SC, a midbrain visual nucleus and direct target of retinal ganglion cells). However, in order to determine the complexity and quality of visual information provided by the transplant visual responsivity must be determined at a greater level of detail and in structures such as higher visual cortex where more complex visual processing occurs. Our main hypothesis is that transplants of fetal- and hESC-derived retinal progenitor sheets will drive complex and specialized visual responses in visual cortex (Aims 1 and 2), as well as visually guided behavior, and, that feedforward and feedback cortical circuitry at the level of specific neuronal cell types will be more similar to normal rats than RD rats without transplants (Aim 3). These studies will be performed using two rat models that are effectively blind by 3 months of age - through a collaboration combining visual neurophysiology expertise and cutting edge neural circuit tracing using genetically modified rabies viruses from the PI with the unrivaled surgical skills for retinal sheet transplantation and expert breeding knowledge of transgenic RD rats by the CO-PI. This project directly addresses the NEI Audacious Goals Initiative to regenerate the eye and visual system.

全世界有数百万人因年龄相关性黄斑变性的进展阶段而丧失视力 和视网膜色素变性。通过这种疾病，大部分视网膜色素上皮（RPE）和许多 光感受器不可逆转地丧失，并且使用营养因子或基因疗法的新的尖端治疗方法， 无效，因为组织不再存在以被拯救。我们的目标是矫正视力丧失 通过将视网膜祖细胞组织片移植到退化的视网膜中。在啮齿动物模型中， 视网膜变性（RD），几项研究表明，视网膜祖细胞片成功地 通过移植视网膜和宿主之间的突触连接，整合到宿主视网膜中，并引起 在上级丘（SC，中脑视觉核团和视网膜电图的直接靶点）中对闪光的反应 神经节细胞）。然而，为了确定视觉信息的复杂性和质量， 移植视觉响应度必须在更高的细节水平和结构中确定， 进行更复杂视觉处理的视觉皮层。 我们的主要假设是，胚胎和hESC衍生的视网膜祖细胞片层的移植将 在视觉皮层中驱动复杂和专门的视觉反应（目标1和2），以及视觉引导 行为，并且，在特定神经元细胞类型的水平上的前馈和反馈皮层电路将被 比没有移植的RD大鼠更类似于正常大鼠（目的3）。这些研究将使用两个 3个月大时有效失明的大鼠模型-通过结合视觉 神经生理学专业知识和尖端神经回路跟踪使用转基因狂犬病病毒从 PI拥有无与伦比的视网膜片移植手术技能和专业的育种知识， 通过CO-PI检测转基因RD大鼠。 这个项目直接解决了NEI大胆的目标倡议，以再生眼睛和视觉 系统