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。

• 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
• 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

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）。青光眼，最 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10%以上失明。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。通过生成人类 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，逆转视神经病变导致的失明。实现 RGC 替代需要大量 确保移植细胞存活并促进其通讯（整合）的能力不断进步 与视觉系统。正在开展大量工作来开发驱动 RGC 神经纤维（轴突）生长的方法 朝向大脑中的视觉中心。然而，移植后 RGC 的存活率以及与其他细胞的沟通 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 移植的人类 RGC 的视网膜整合。为此，他将提出三个具体目标：（1）一代 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 参与 RGC 死亡和神经保护的分子途径； (2)视神经如何测定 神经退行性疾病状态会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障碍并开发方法 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 在约翰·霍普金斯大学威尔默眼科研究所的杰出研究环境下， 由高级研究人员组成的跨学科团队，包括博士。唐·扎克、哈里·奎格利和亚历克斯·科洛德金。超过 五年内，他将获得新兴分子生物学和神经科学技术所需的专业知识 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。