Transplantation of human stem cell-derived neurons for retinal ganglion cell replacement and optic nerve regeneration.

项目概要/摘要 视神经病变导致不可逆的视力丧失，因为人类和其他哺乳动物不能修复视神经。 神经或重新填充构成它的神经细胞（视网膜神经节细胞或RGC）。青光眼，最 常见的视神经病变，预计到2040年将影响超过1.1亿人， 失明率超过10%。干细胞疗法在治疗神经退行性疾病方面具有巨大潜力 目前无法治愈的疾病，包括青光眼和其他视神经病变。通过生成人类 将RGCs放入培养皿中并将其移植到眼睛中，可能会取代丢失的RGCs，再生 视神经和视神经病变引起的反向失明。要取代研资局， 我们确保移植细胞存活并促进其交流（整合）的能力的进步 视觉系统。正在进行重要的工作，以开发驱动RGC神经纤维（轴突）生长的方法 大脑中的视觉中心。然而，移植后RGC的存活率和与其他组织的沟通， 视网膜中的神经元（即双极细胞和无长突细胞）同样重要，但研究较少。 通过这个指导临床医生-科学家职业发展项目，托马斯约翰逊博士建议 通过提高存活率来推进干细胞移植用于视神经再生的领域， 移植的人RGC的视网膜整合。为此，他将提出三个具体目标：（1）代 新的人类细胞系的基因工程，以提高移植后的生存率， 参与RGC死亡和神经保护的分子通路;（2）确定视神经如何 神经退行性疾病状态影响移植到眼睛中的RGC的存活和整合;和（3） 阐明移植的RGC如何感知视网膜整合的障碍，并开发用于治疗的方法。 克服这些障碍。拟议的工作将解决先前平移视神经的关键限制 再生研究通过使用更适用于人类疾病的实验模型， 移植结果评估的实验严谨性，确定哪些RGC亚型最有可能 存活和整合，并控制从移植细胞到受体视网膜的“物质转移”。 博士约翰逊是一位早期职业青光眼专家和神经科学家，他将在一个 杰出的研究环境在约翰霍普金斯的威尔默眼科研究所，指导下， 跨学科团队的高级研究人员，包括博士唐扎克，哈利奎格利，和亚历克斯Kolodkin。超过 五年内，他将获得新兴分子生物学和神经科学技术的专业知识， 实现他的长期目标：领导独立的高影响力视神经再生研究 实验室，为青光眼患者提供出色的医疗和手术护理;并弥合差距 通过RGC帮助开创青光眼治疗的新时代， 替代和视神经再生。

Project Summary / Abstract Optic neuropathy causes irreversible vision loss because humans and other mammals cannot repair the optic nerve or repopulate the nerve cells that comprise it (retinal ganglion cells or RGCs). Glaucoma, the most common optic neuropathy, is projected to affect more than 110 million people by 2040, and to cause bilateral blindness in more than 10% of them. Stem cell therapy holds great potential for treating neurodegenerative diseases that currently have no cure, including glaucoma and other optic neuropathies. By generating human RGCs in a dish and transplanting them into the eye, it might be possible to replace lost RGCs, regenerate the optic nerve, and reverse blindness from optic neuropathy. Achieving RGC replacement will require significant advances in our ability to ensure survival of transplanted cells and facilitate their communication (integration) with the visual system. Significant work is ongoing to develop methods to drive RGC nerve fiber (axon) growth towards visual centers in the brain. However, RGC survival after transplantation and communication with other neurons in the retina (i.e. bipolar and amacrine cells) are equally important and have been less well studied. Through this mentored clinician-scientist career development project, Dr. Thomas Johnson proposes to advance the field of stem cell transplantation for optic nerve regeneration by improving survival and retinal integration of transplanted human RGCs. To so, he will address three specific aims: (1) Generation of novel human cell lines genetically engineered for improved survival after transplantation by targeting molecular pathways involved in RGC death and neuroprotection; (2) Determination of how optic nerve neurodegenerative disease states affect survival and integration of RGCs transplanted into the eye; and (3) Elucidation of how transplanted RGCs sense barriers to retinal integration and development of methods for overcoming these obstacles. The proposed work will address key limitations of prior translational optic nerve regeneration research by using experimental models that are more applicable to human disease, increasing the experimental rigor of transplant outcome assessments, determining which RGC subtypes are most likely to survive and integrate, and controlling for “material transfer” from transplanted cells to the recipient retina. Dr. Johnson is an early-career glaucoma specialist and neuroscientist who will conduct this project in an outstanding research environment at Johns Hopkins’ Wilmer Eye Institute, under the mentorship of an interdisciplinary team of senior investigators, including Drs. Don Zack, Harry Quigley, and Alex Kolodkin. Over five years he will acquire expertise in emerging molecular biology and neuroscience techniques required for achieving his long-term goals of: leading an independent high-impact optic nerve regeneration research laboratory, providing outstanding medical and surgical care to patients with glaucoma; and bridging the gap between the clinic and laboratory by helping to usher in a new era of glaucoma treatment though RGC replacement and optic nerve regeneration.