Functional plasticity in retinal degenerative disease

视网膜退行性疾病的功能可塑性

基本信息

  • 批准号:
    10637293
  • 负责人:
  • 金额:
    $ 38.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

During the last two decades it has become clear that the retina is not just a static network of neurons. Retinal neurons change their properties and connections during aging or disease in a process termed retinal remodeling or plasticity. However, mechanisms that mediate plasticity, as well as the impact of plasticity on light signaling in the retina and vision are still poorly defined. Our long-term goal is to advance the field of retinal remodeling towards development of vision restoration therapies with improved outcomes. This goal is achieved by (i) determining compensatory mechanisms in the retina that can promote vision, and (ii) quantifying the impact of remodeling on the retinal output and vision during photoreceptor degenerative disease. Our central hypothesis is that a partial loss of sensory input from rods increases the gain of transmission of the remaining input to rod bipolar cells (RBCs) in the retina to promote vision, whereas extensive loss of the sensory input leads to a corruption of the light signal transmission and exacerbation of vision loss. This central hypothesis will be tested in a mouse model of autosomal dominant retinitis pigmentosa caused by the rhodopsin P23H mutation. The rationale of this project is that delineating a compensatory mechanism in the retina will yield an accessible target for promoting vision in photoreceptor degenerative diseases where this does not happen naturally. Secondly, new knowledge about the impact and time course of constructive and destructive remodeling in the retina on vision will generate critical information about the expected outcomes of vision restoration therapies. The central hypothesis will be tested in two specific aims: 1) Determine the mechanism underlying the increase of rod - RBC signal transmission at early stages of retinal degenerative disease; and 2) Determine the impact of inner retinal remodeling on light signal transmission during photoreceptor degenerative disease. In the first aim, a working hypothesis that rod – RBC transmission is potentiated in P23H mice via synaptotagmin-1 (Syt1)-dependent pathway in rod synaptic terminal will be tested by using P23H mice with a rod-specific deletion of Syt1 and in vivo/ex vivo Electroretinogram as well as patch clamp physiology. In addition, these mice will be used to determine the impact of this compensatory mechanism on vision using behavior methods. In the second aim, genetic silencing of photoreceptors and optogenetics will be used together with ganglion cell multielectrode array electrophysiology in P23H mice to evaluate the impact of inner retina remodeling on ganglion cell output during photoreceptor degeneration from early to late-stage disease. This innovative work 1) challenges current dogma of destructive remodeling by asserting that in some retinal degenerative diseases, the retina compensates for the loss of photoreceptors to maintain stable output and vision; and 2) applies genetic and optogenetic tools to determine the causal role of remodeling on retinal output signal and vision. The proposed research is significant because it will transform our understanding of plasticity in the retina and how it impacts retinal function and vision, critical knowledge required for restoring normal vision at different stages of blinding disease.
在过去的二十年里,人们已经清楚地认识到视网膜不仅仅是一个静态的神经元网络。视网膜 在老化或疾病过程中,神经元改变其特性和连接,这一过程称为视网膜重塑 或可塑性。然而,介导可塑性的机制,以及可塑性对光信号的影响, 视网膜和视力仍然不清楚。我们的长期目标是推进视网膜重塑领域 致力于发展视力恢复疗法,改善疗效。实现这一目标的途径是:(一) 确定视网膜中可以促进视力的补偿机制,以及(ii)量化 感光细胞退行性疾病期间视网膜输出和视力的重塑。我们的核心假设 部分失去来自视杆细胞的感觉输入会增加其余输入传递到视杆细胞的增益 双极细胞(红细胞)在视网膜,以促进视力,而广泛的损失的感觉输入导致 光信号传输的恶化和视力丧失的恶化。这一中心假设将得到检验 在由视紫红质P23 H突变引起的常染色体显性视网膜色素变性小鼠模型中。的 该项目的基本原理是,描绘视网膜中的补偿机制将产生一个可及的目标 用于促进感光细胞变性疾病的视力,而这不是自然发生的。第二、 关于视网膜建设性和破坏性重塑的影响和时间进程的新知识, 视力将产生关于视力恢复治疗的预期结果的关键信息。中央 将在两个具体目标中检验这一假设:1)确定杆- RBC增加的潜在机制 视网膜退行性疾病早期的信号传递;和2)确定视网膜内层的影响。 光感受器退行性疾病对光信号传递的影响。在第一个目标中, 假设P23 H小鼠视杆细胞-红细胞传递通过突触结合蛋白-1(Syt 1)依赖性 将通过使用具有Syt 1的视杆特异性缺失的P23 H小鼠和在视杆突触末端中的P23 H小鼠来测试视杆突触末端中的信号通路。 体内/离体视网膜电图以及膜片钳生理学。此外,这些小鼠将用于 使用行为方法确定这种补偿机制对视觉的影响。第二个目标, 光感受器的遗传沉默和光遗传学将与神经节细胞多电极阵列一起使用 在P23 H小鼠中进行电生理学检查,以评估在P23 H小鼠中视网膜内重塑对神经节细胞输出的影响。 光感受器退化从早期到晚期的疾病。这项创新的工作挑战了当前的教条 破坏性重塑的断言,在一些视网膜退行性疾病,视网膜补偿 光感受器的损失,以保持稳定的输出和视力;和2)应用遗传和光遗传学工具, 确定重塑对视网膜输出信号和视力的因果作用。所提出的研究是有意义的 因为它将改变我们对视网膜可塑性的理解,以及它如何影响视网膜功能, 视力,在致盲疾病的不同阶段恢复正常视力所需的关键知识。

项目成果

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Frans Vinberg其他文献

Frans Vinberg的其他文献

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{{ truncateString('Frans Vinberg', 18)}}的其他基金

Pigment Regeneration Mechanisms in the Human Retina
人类视网膜色素再生机制
  • 批准号:
    10671007
  • 财政年份:
    2020
  • 资助金额:
    $ 38.48万
  • 项目类别:
Pigment Regeneration Mechanisms in the Human Retina
人类视网膜色素再生机制
  • 批准号:
    10033250
  • 财政年份:
    2020
  • 资助金额:
    $ 38.48万
  • 项目类别:
Pigment Regeneration Mechanisms in the Human Retina
人类视网膜色素再生机制
  • 批准号:
    10259840
  • 财政年份:
    2020
  • 资助金额:
    $ 38.48万
  • 项目类别:
Pigment Regeneration Mechanisms in the Human Retina
人类视网膜色素再生机制
  • 批准号:
    10450119
  • 财政年份:
    2020
  • 资助金额:
    $ 38.48万
  • 项目类别:
Assessment of Retinal Function in Health and Disease From Mouse To Human
评估从小鼠到人类的健康和疾病中的视网膜功能
  • 批准号:
    9535533
  • 财政年份:
    2017
  • 资助金额:
    $ 38.48万
  • 项目类别:
ASSESSMENT OF RETINAL FUNCTION IN HEALTH AND DISEASE FROM MOUSE TO HUMAN
从小鼠到人类的健康和疾病中的视网膜功能评估
  • 批准号:
    9249586
  • 财政年份:
    2016
  • 资助金额:
    $ 38.48万
  • 项目类别:
ASSESSMENT OF RETINAL FUNCTION IN HEALTH AND DISEASE FROM MOUSE TO HUMAN
从小鼠到人类的健康和疾病中的视网膜功能评估
  • 批准号:
    9088931
  • 财政年份:
    2016
  • 资助金额:
    $ 38.48万
  • 项目类别:

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