Retinal Ganglion Cell Replacement in Optic Neuropathies

视神经病变中的视网膜神经节细胞替代

基本信息

批准号：
10239017
负责人：
David J. Calkins
金额：
$ 135.75万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239017
关键词：
ATOH7 gene Animals Autopsy Axon Axonal Transport Biological Assay Blindness Brain Cell Death Cell Nucleus Cell Transplantation Cells Clustered Regularly Interspaced Short Palindromic Repeats Data Diagnosis Distal Dose Electrophysiology (science)Electroretinography Evoked Potentials Fluorescence Gene Expression Glaucoma Goals Growth Histologic Histology Human Image Implant In Vitro Injections Injury Institution Label Laboratories Light Measures Mediating Membrane Microspheres Modality Modeling Molecular Monkeys Ophthalmoscopy Optic Nerve Optical Coherence Tomography Pathway interactions Patients Photons Photosensitivity Physiologic Intraocular Pressure Physiology Property Protocols documentation Research Resolution Retina Retinal Ganglion Cells Risk Factors Rodent Rodent Model Saimiri Scanning Shipping Ships Signal Transduction Structure Testing Translations Transplantation Visual system structure adaptive optics axonopathy cell replacement therapy cohort fluorophore fundus imaging human embryonic stem cell human embryonic stem cell line human stem cells in vivo innovation melanopsin migration neurite growth nonhuman primate notch protein optic nerve disorder portability progenitor programs regeneration potential sight restoration standard of care synaptogenesis therapeutic development transcription factor transcriptome translation to humans transplant model visual dysfunction

项目摘要

PROJECT SUMMARY Glaucoma is a leading causes of blindness and along with other optic neuropathies is characterized by the loss of retinal ganglion cells (RGCs). Increased intraocular pressure (IOP) management is the current standard of care for glaucoma patients, but fails to stop the irreversible loss of RGCs and progressive visual dysfunction. Vision restoration through RGC replacement therapy, one of the NEI’s Audacious Goals program, could be a potential solution, and considerable progress has been made in understanding the molecular signals that regulate RGC specification from human stem cells, as well as in RGC transplant and integration in rodents. However, when considering translation of laboratory advances to human testing, rodent models are limited by critical differences in retinal physiology, and proof-of-concept in non-human primates would greatly increase confidence and aid in therapeutic development before moving to human testing. Thus there is a considerable need for a tractable non-human primate model. Here we will establish a squirrel monkey-induced glaucoma model and the parameters to study human stem cell-derived RGC integration and potential vision restoration in a retina and visual system closer to those of human. Through this 5-year proposal we will achieve critical milestones, including validating the monkey glaucoma model, studying key structural and functional measures using innovative new modalities that should be portable between monkey and humans, and demonstrating the model’s ability to move across institutions. All of this will be accomplished in the setting of studying RGC transplant: differentiation, migration, local integration and synapse formation, growth down the optic nerve, and targeting to distal brain nuclei, with the goal of vision restoration.

项目摘要青光眼是失明的主要原因，以及其他视神经病的特征视网膜神经节细胞（RGC）的丧失。眼内压力（IOP）管理是电流青光眼患者的护理标准，但无法阻止RGC的不可逆转损失和进行性视觉损失功能障碍。通过RGC替代疗法进行视觉恢复，这是NEI大胆的目标计划之一，可能是一个潜在的解决方案，并且在理解分子方面取得了很大进展从人类干细胞以及RGC移植中调节RGC规范的信号以及在啮齿动物。但是，当考虑将实验室进步转换为人类测试时，啮齿动物模型是受到视网膜生理学的关键差异的限制，非人类灵长类动物的概念证明将大大限制在进行人体测试之前，请提高对热发育的信心和帮助。有一个非常需要易于处理的非人类私人模型。在这里，我们将建立一个松鼠猴引起的青光眼模型和研究人类干细胞衍生的RGC整合和潜在视觉的参数在视网膜和视觉系统中恢复更接近人类的系统。通过这个为期5年的建议，我们将实现关键里程碑，包括验证猴子青光眼模型，研究关键结构和使用创新的新方式应在猴子和人类之间便携的创新新模式，并展示该模型跨机构的能力。所有这些都将在环境中完成研究RGC移植：分化，迁移，局部整合和突触形成，逐渐降低视神经的视神经，靶向远端脑核，以恢复视觉恢复。