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

基本信息

批准号：
10446188
负责人：
David C Lyon
金额：
$ 59.51万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/10446188
关键词：
3-Dimensional Address Age Age related macular degeneration Age-Months Anatomy Animal Model Animals Anterior Area Behavior Blindness Breeding Cell Nucleus Cells Clinical Collaborations Complex Conscious Cues Data Disease Dorsal Electrocorticogram Eye Feedback Frequencies Generations Goals Histologic Human Image Knowledge Label Lateral Lead Light Maintenance Medial Methods Microelectrodes Midbrain structure Modeling Natural regeneration 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 Short Interspersed Nucleotide Elements 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 structure advanced disease area striata behavior test blind cell type college excitatory neuron experimental study extrastriate visual cortex fetal flexibility gene therapy human embryonic stem cell human tissue image processing ineffective therapies inhibitory neuron neural circuit neurophysiology preference progenitor rabies viral tracing response retina transplantation retinal progenitor cell retinal regeneration rho sight restoration skills superior colliculus Corpora quadrigemina visual information visual processing

项目摘要

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.

全球有数百万人因年龄相关性黄斑变性的进展阶段而遭受视力丧失和色素性视网膜炎。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地丢失，使用营养因子或基因疗法的新尖端治疗方法正在出现无效，因为组织不再存在可被抢救。我们的目标是修复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），多项研究表明，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，并诱发上丘（SC，中脑视觉核和视网膜的直接目标）对闪光的反应神经节细胞）。然而，为了确定视觉信息提供的复杂性和质量移植视觉反应性必须在更详细的水平和结构中确定，例如更高的视觉皮层进行更复杂的视觉处理。我们的主要假设是，胎儿和 hESC 来源的视网膜祖细胞片的移植将驱动视觉皮层中复杂且专门的视觉反应（目标 1 和 2），以及视觉引导行为，并且特定神经元细胞类型水平的前馈和反馈皮质电路将比未移植的 RD 大鼠更类似于正常大鼠（目标 3）。这些研究将使用两个通过与视觉相结合的合作，在 3 个月大时实际上失明的大鼠模型神经生理学专业知识和尖端神经回路追踪，使用转基因狂犬病病毒 PI 拥有无与伦比的视网膜片移植手术技巧和专家育种知识 CO-PI 的转基因 RD 大鼠。该项目直接针对 NEI 大胆目标计划，以再生眼睛和视觉系统。