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.

项目摘要 /摘要视力神经病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光学神经或重新填充包含它的神经细胞（视网膜神经节细胞或RGC）。青光眼，最多普通的视神经病变预计到2040年将影响超过1.1亿的人，并引起双侧超过10％的失明。干细胞疗法具有治疗神经退行性的巨大潜力目前尚无治愈的疾病，包括青光眼和其他视神经病。通过产生人类 RGC中的菜肴中的RGC并将其移植到眼睛中，可能会更换丢失的RGC，再生视神经和视神经病的反向失明。实现RGC更换将需要大量我们确保移植细胞生存并促进其交流的能力的进步（整合）使用视觉系统。正在进行重要的工作，以开发驱动RGC神经纤维（Axon）生长的方法朝向大脑的视觉中心。但是，移植和与其他人交流后的RGC生存视网膜中的神经元（即双极细胞和无长血管细胞）同样重要，并且研究不善。通过这个修订的临床科学家职业发展项目，托马斯·约翰逊博士提案通过改善生存和移植的人RGC的视网膜整合。为此，他将解决三个具体目标：（1）一代新型人类细胞系的基因设计，可通过靶向移植后提高生存率参与RGC死亡和神经保护的分子途径；（2）确定视神经如何神经退行性疾病状态会影响移植到眼睛的RGC的存活和整合。（3）阐明如何移植的RGC感知遗传障碍，以使剩余整合和开发方法的发展克服这些障碍。拟议的工作将解决先前翻译视神经的关键局限性再生研究通过使用更适用于人类疾病的实验模型，增加移植结果评估的实验严格性，确定哪些RGC亚型最有可能生存和整合，并控制从移植细胞到受体视网膜的“材料转移”。约翰逊博士是一位早期的青光眼专家和神经科学家，他将在约翰·霍普金斯（Johns Hopkins）威尔默眼科研究所（Wilmer Eye Institute）的杰出研究环境高级调查员的跨学科团队，包括Drs。 Don Zack，Harry Quigley和Alex Kolodkin。超过五年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；并弥合差距在诊所和实验室之间，通过RGC来帮助迎接青光眼治疗的新时代替代和视神经再生。