Visualizing functional retinal integration of transplanted retinal ganglion cells

移植视网膜神经节细胞的功能性视网膜整合可视化

基本信息

  • 批准号:
    10510837
  • 负责人:
  • 金额:
    $ 24.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-30 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Functional retinal ganglion cell (RGC) replacement could restore vision to tens of millions of people who are blind from glaucoma and other optic neuropathies. Establishment of techniques for RGC differentiation from pluripotent stem cells and the achievement of long-distance endogenous axon regeneration within the optic nerve support the promise of RGC replacement therapies. However, clinical translation requires significant improvements in the functional integration of transplanted RGCs into the host retinal neurocircuitry. To enable the study of synaptogenesis by transplanted neurons, we propose developing and validating an innovative, versatile, sensitive, experimental tool that leverages transsynaptic transport of wheat germ agglutinin (WGA) protein fused to Cre recombinase to enable expression of a Cre-dependent reporter in synaptically integrated donor neurons. The label is durable, facilitating downstream applications such as single cell isolation and transcriptomic analysis, and bidirectional to allow the labeling of either pre- or post-synaptic graft-host neuronal partners. Here, we propose to establish human pluripotent cell lines to be used in conjunction with highly efficient recombinant AAV vectors to report the functional retinal of transplanted RGCs. Since expression of the fluorescent reporter is automatic upon genomic recombination, the tool will facilitate real-time detection of functional neuronal integration in vivo. We propose a short wavelength (blue) fluorescent reporter for synaptogenesis, which will be compatible with additional red and green fluorescence for multicolor microscopy and ophthalmoscopy. We will characterize the kinetics of expression and validate the specificity of this synaptogenesis reporter tool using a combination of high-resolution confocal microscopy, immunolabeling of synaptic machinery, and single-cell electrophysiology within retinal flatmounts. Further, we will study the functional integration of transplanted human RGCs in vivo using a custom-built multicolor adaptive optics scanning laser ophthalmoscope. The instrumentation provides subcellular resolution within in the xy plane and depth discrimination with the retina through z-stacking. Longitudinal imaging of living eyes post- transplantation will therefore enable the correlation of donor RGC dendrites targeting of the inner plexiform layer with reporting of functional synaptogenesis. We will characterize the structural events leading to retinal integration of donor RGCs. This work will provide a foundation for future experimentation that includes manipulation of the host microenvironment to improve engraftment efficiency, in vivo optical electrophysiology of integrated RGCs, and robust analyses of RGC interactions with various resident retinal cells using cell-specific reporter mice.
项目总结

项目成果

期刊论文数量(0)
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Thomas Vincent Johnson其他文献

Thomas Vincent Johnson的其他文献

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{{ truncateString('Thomas Vincent Johnson', 18)}}的其他基金

RReSTORE: RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration.
RReSTORE:RGC 重建、干细胞移植和视神经再生。
  • 批准号:
    10469156
  • 财政年份:
    2022
  • 资助金额:
    $ 24.56万
  • 项目类别:
Visualizing functional retinal integration of transplanted retinal ganglion cells
移植视网膜神经节细胞的功能性视网膜整合可视化
  • 批准号:
    10707349
  • 财政年份:
    2022
  • 资助金额:
    $ 24.56万
  • 项目类别:
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:
    10469468
  • 财政年份:
    2020
  • 资助金额:
    $ 24.56万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 24.56万
  • 项目类别:
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:
    10039636
  • 财政年份:
    2020
  • 资助金额:
    $ 24.56万
  • 项目类别:

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