Photoreceptor Regeneration in a Murine Model of Leber Congenital Amaurosis

莱伯先天性黑蒙小鼠模型中的光感受器再生

基本信息

批准号：
10674727
负责人：
Katherine Elizabeth Uyhazi
金额：
$ 23.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674727
关键词：
Address Age related macular degeneration Animals Blindness Cell Cycle Cell Death Cell Therapy Cell Transplantation Cells Chemicals Childhood Complementary DNA Complex Cues DNA Sequence Alteration Development Disease Disease model Dissociation Electroretinography Environment Eye FDA approved Foundations GLAST Protein Genes Genetic Heterogeneity Histology Human Image Immunofluorescence Immunologic Injury Label Lead Leber&apos s amaurosis Leber&apos s disease Mediating Mendelian disorder Mentorship Modeling Molecular Muller&apos s cell Mus Mutation Natural regeneration Neuroglia Ophthalmology Optical Coherence Tomography Papain Pathway interactions Patients Pennsylvania Photoreceptors Physicians Population Predisposition RNA RPE65 protein Regenerative capacity Reporter Reporting Research Resources Retina Retinal Degeneration Retinal Diseases Safety Scientist Severities Sorting Stem cell pluripotency Stem cell transplant Structure Testing Therapeutic Time Training Transplantation Universities Vision Zebrafish alternative treatment behavior test career cell type early onset functional improvement gene product gene therapy human disease improved in vivo in vivo regeneration inherited retinal degeneration mouse model neonatal mice novel postnatal precursor cell preservation progenitor pup regenerative repaired retinal neuron retinal progenitor cell retinal regeneration retinal stimulation retinogenesis sight restoration single-cell RNA sequencing skills stem cells transcription factor transcriptomics vector viral gene delivery

项目摘要

PROJECT TITLE Photoreceptor Regeneration in a Murine Model of Leber Congenital Amaurosis ABSTRACT Leber congenital amaurosis (LCA) is an early-onset, severe inherited retinal degeneration that results in childhood blindness. Gene therapy can effectively restore visual function in the Lca5gt/gt mouse model of the disease when delivered to neonatal mice before significant retinal degeneration is present. However, in moderate- and late- stage disease after photoreceptor cell death has occurred, gene therapy is no longer effective. Cell-based therapies hold great promise for regenerating photoreceptors in late-stage retinal degenerations, but progress has been limited by low efficiencies of integration and complex cellular interactions with existing retinal cells. Photoreceptor precursors represent a heterogeneous pool of diverse cells types that have the potential to differentiate into mature photoreceptor cells in the developing and diseased retina. Using unbiased single-cell RNA transcriptomics, I identified several novel populations of Crx+ photoreceptor precursors including Crx+/Nfix+ and Crx+/Slc39a1+ cells. The scientific objectives of this proposal are to regenerate photoreceptors in the Lca5gt/gt mouse model of retinal degeneration, by the transplantation of these novel populations of photoreceptor precursors and by the activation of endogenous repair pathways in Müller glia. The Aims of the proposal are 1) Subretinal transplantation of Crx+/Nfix+ and Crx+/Slc39a1+ progenitor cells in Lca5gt/gt mice, and 2) Activation of endogenous Müller glial repair pathways by gene therapy in Lca5gt/gt mice. In addition to these scientific contributions, this proposal outlines a structured, focused training plan that will equip me with the skills and expertise that will serve as the foundation for my career in developing cell-based therapies for retinal disease. The Department of Ophthalmology at the University of Pennsylvania is an ideal environment for training physician scientists in ophthalmic research, and will provide the protected time, resources, and mentorship needed for a successful transition to independence.

项目标题光感受器再生在Leber先天性阿莫菌的鼠模型中抽象的 Leber先天性弹药（LCA）是一种早期，严重的遗传性变性，导致童年的失明。基因疗法可以有效地恢复LCA5GT/GT小鼠模型的视觉功能疾病在存在明显的残留变性之前递送到新生小鼠时。但是，在感光细胞死亡发生后中度和晚期疾病，基因治疗不再是有效的。基于细胞的疗法对在后期视网膜中再生感受器的再生有很大的希望退化，但由于整合效率低和复杂的细胞，进展受到限制与现有永久细胞的相互作用。感光细胞前体代表有潜力的潜水细胞类型的异质池分化为发育中和解散的视网膜中成熟的感光细胞。使用公正的单细胞 RNA转录组学，我确定了几个新的CRX+光感受器前体，包括 CRX+/NFIX+和CRX+/SLC39A1+细胞。该提议的科学目标是重生通过移植这些新型的LCA5GT/GT小鼠模型中的光感受器光感受器前体的种群以及通过穆勒胶质中的内源性修复途径的激活。该提案的目的是1）CRX+/NFIX+和CRX+/SLC39A1+祖细胞的视网膜下移植 LCA5GT/GT小鼠和2）通过LCA5GT/GT小鼠的基因治疗激活内源性müller神经胶质修复途径。除了这些科学贡献外，该提案还概述了一个结构化的，重点的培训计划为我提供技能和专业知识，这将是我开发基于细胞的职业的基础残留疾病的疗法。宾夕法尼亚大学眼科系是理想的培训眼科研究的物理科学家的环境，并将提供受保护的时间成功过渡到独立性所需的资源和精神训练。