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

移植人类干细胞衍生的神经元，用于视网膜神经节细胞替代和视神经再生。

基本信息

批准号：
10249198
负责人：
Thomas Vincent Johnson
金额：
$ 18.92万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10249198
关键词：
3-Dimensional Address Affect Amacrine Cells Anatomy Astrocytes Bilateral Blindness Brain Brain-Derived Neurotrophic Factor Cadherins Caring Cell Communication Cell Death Cell Differentiation process Cell Line Cell Nucleus Cell Survival Cell Transplantation Cells Chronic Clinic Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communication Complex Cues Dendrites Development Disease Electrophysiology (science)Engineering Engraftment Ensure Environment Experimental Models Extracellular Matrix Eye Funding Future Ganglion Cell Layer Gene Expression Generations Genetic Engineering Glaucoma Gliosis Goals Graft Survival Human Human Cell Line Human Engineering Institutes Integrins Laboratories Laboratory Research Mammals Mediating Medical Membrane Mentors Mentorship Methods Microscopy Modeling Molecular Molecular Biology Molecular Target Mus Natural regeneration Nerve Crush Nerve Degeneration Nerve Fibers Neurites Neurodegenerative Disorders Neuroglia Neurons Neurosciences Ocular Hypertension Operative Surgical Procedures Ophthalmology Optic Nerve Optic Nerve Injuries Outcome Outcome Assessment Pathway interactions Patients Pharmacology Property Regenerative research Reporter Repression Research Research Personnel Retina Retinal Ganglion Cells Scientist Secondary to Signal Pathway Signal Transduction Site Specialist Stem cell transplant Surface Synapses Techniques Testing Tissues Training Training Programs Transgenic Organisms Translating Translational Research Transplantation Visual Visual system structure Work axon growth axon guidance axon regeneration career career development experimental study human disease human stem cells improved improved outcome in vivo in vivo evaluation innovation method development migration multiphoton microscopy nerve damage neuroinflammation neuronal cell body neuronal patterning neuronal survival neuroprotection novel optic nerve disorder optic nerve regeneration patch clamp receptor reconstruction relating to nervous system repaired retina transplantation retinal neuron retinal progenitor cell sight restoration skills stem cell therapy stem cells synaptogenesis

项目摘要

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.

项目概要/摘要视神经病变会导致不可逆的视力丧失，因为人类和其他哺乳动物无法修复视神经神经或重新填充组成它的神经细胞（视网膜神经节细胞或 RGC）。常见视神经病变，预计到 2040 年将影响超过 1.1 亿人，并导致双眼视神经病变其中超过 10% 的人失明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。将 RGC 放入培养皿中并将其移植到眼睛中，也许可以替代丢失的 RGC，从而再生视神经，并扭转视神经病变导致的失明需要大量的治疗。确保移植细胞存活并促进其沟通（整合）的能力不断进步与视觉系统相关的重要工作正在开发驱动 RGC 神经纤维（轴突）生长的方法。然而，RGC 移植后仍能存活并与其他器官进行交流。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。通过这个受指导的临床医生-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和促进视神经再生干细胞移植领域的发展为此，他将解决三个具体目标：（1）生成。通过基因工程改造新型人类细胞系，通过靶向提高移植后的存活率 (2)视神经如何测定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；以及 (3) 阐明移植的 RGC 如何感知视网膜整合障碍并开发方法克服这些障碍所提出的工作将解决先前平移视神经的关键局限性。通过使用更适用于人类疾病的实验模型进行再生研究，增加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”。约翰逊博士是一位职业生涯早期的青光眼专家和神经科学家，他将在一个约翰·霍普金斯大学威尔默眼科研究所拥有出色的研究环境，在一位专家的指导下由唐·扎克 (Don Zack)、哈里·奎格利 (Harry Quigley) 和亚历克斯·科洛德金 (Alex Kolodkin) 博士组成的跨学科团队。五年内，他将获得新兴分子生物学和神经科学技术方面的专业知识实现他的长期目标：领导一项独立的高影响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缩小差距；通过 RGC 帮助开创青光眼治疗的新时代，在诊所和实验室之间建立联系置换和视神经再生。