Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma

克服实验性青光眼视网膜神经节细胞替代的障碍

• 批准号: 10875042
• 负责人: BRAD FORTUNE
• 金额: $ 9.34万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10875042
• 关键词: Address; Age; Anatomy; Astrocytes; Axon; Biology; Blindness; Brain; Cell Differentiation process; Cell Line; Cell Survival; Cells; Characteristics; Communities; Complex; Data Set; Development; Disease; Donor person; Electrophysiology (science); Engraftment; Environment; Experimental Models; Eye; FRAP1 gene; Future; Gene Expression Profile; Genetic; Glaucoma; Goals; Human; Immunosuppressive Agents; Knowledge; Modeling; Molecular; Nerve Regeneration; Neuroglia; Neurons; Optic Nerve; Output; Persons; Process; Rejuvenation; Research; Research Personnel; Resources; Retina; Retinal Degeneration; Retinal Ganglion Cells; Series; Signal Transduction; Site-Directed Mutagenesis; Testing; Therapeutic; Thrombospondins; Translations; Transplantation; Viral Vector; Vision Disorders; Visual; Visual System; Visual impairment; Visually Impaired Persons; Work; cell injury; cellular development; clinically relevant; designer receptors exclusively activated by designer drugs; experimental study; ganglion cell; glial activation; improved; induced pluripotent stem cell; innovation; neuroinflammation; neuronal replacement; neurotoxic; novel; novel strategies; optic nerve disorder; overexpression; receptor; repaired; retina transplantation; retinal ganglion cell degeneration; retinal neuron; sight restoration; sound; synaptogenesis; tool; translational approach; transmission process

Project Summary / Abstract Retinal ganglion cells (RGCs) are the output neurons of the retina responsible for transmitting information about the visual world from the eye to the brain. Thus, RGC damage and loss, a characteristic of many disorders of the visual system, has the direct consequence of vision impairment, or blindness when RGC loss is more severe. Our translation-enabling approach builds on a very well-established, thoroughly characterized and validated experimental glaucoma (EG) model. This affords our study the distinct advantage of conducting each of the proposed hypothesis-driven experiments within the framework of a reliable model of RGC degeneration that closely recapitulates the anatomical changes and pathophysiological processes observed in human glaucoma. Moreover, our preliminary results establish the feasibility of our approach, demonstrating that we have already achieved successful transplantation of human induced pluripotent stem cell (iPSC)-derived RGCs into the EG retina, while also characterizing major barriers that require targeted solutions. Hence, we propose to employ a series of manipulations to both donor RGCs and the recipient EG retina in order to overcome the existing barriers to RGC replacement and thus make a giant leap forward toward realization of the audacious goal to restore vision in persons blinded by glaucoma or other optic neuropathies. Each of our Aims is soundly based on existing knowledge of the relevant biology and will lead to meaningful enhancement of donor RGC survival, integration, and function in the glaucomatous EG retina. We will utilize rigorous quantitative electrophysiological and anatomical assessments for testing the hypothesis at the core of each Aim. Aim 1 will target neuroinflammation to improve the long-term survival of transplanted RGCs. We will create hypoimmunogenic iPSCs and manipulate the host retinal environment using systemic immunosuppressive agents or inhibition of microglial activation. Aim 2 will augment donor cell survival and integration through modulation of cellular age, with host retinal glia experimentally induced to an immature state through cellular rejuvenation. Aim 3 will enhance the connectivity and axon outgrowth of donor RGCs in the retina. Donor RGCs will be edited to express hM3Dq DREADD receptors for chemogenetic stimulation and mTOR activators. Thrombospondin will be overexpressed in host retinal astrocytes and donor RGCs, leveraging astrocyte-derived factors that promote axonal outgrowth and synaptogenesis. Together, these Aims will generate a wealth of knowledge and resources for the scientific community and bring us significantly closer to the reality of vision restoration through RGC replacement.

项目摘要/摘要