Stimulation of Retinal Regeneration

刺激视网膜再生

基本信息

批准号：
10656024
负责人：
THOMAS A REH
金额：
$ 40.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656024
关键词：
Address Adopted Adult Affect Age related macular degeneration Amacrine Cells Amphibia Animal Model Blindness Cells Central Nervous System Degenerative Disorder Development Disease Environment Fishes Functional Regeneration Glaucoma Goals HDAC4 gene Human Inflammatory Response Injury Knowledge Macular degeneration Mammals Mediating Methods Minority Mitotic Molecular Muller&apos s cell Mus N-Methylaspartate Natural regeneration Nerve Degeneration Nerve Regeneration Neuroglia Neurons Patients Persons Process Protocols documentation Regenerative response Regulator Genes Retina Retinal Cone Retinal Degeneration Retinal Diseases Signal Pathway Signal Transduction Signaling Molecule Source Stem cell transplant Testing Time Trauma Vertebrates Vision Visual impairment cell regeneration cell type effective therapy experimental study functional restoration in vivo islet molecular phenotype neurogenesis neuron loss neuron regeneration progenitor programs regeneration potential regenerative regenerative therapy repaired retinal damage retinal neuron retinal progenitor cell retinal regeneration retinal stimulation stem cells transcription factor

项目摘要

Abstract Currently, there are no effective therapies to replace degenerated neurons in patients with retina neuron loss from degenerative diseases, such as occurs in patients with glaucoma and macular degeneration. By contrast, retinas of non-mammalian vertebrates, such as fish and amphibians, show a robust regenerative response following retinal damage. Upon injury to the retina, fish Muller Glia generate all different types of retinal neurons to replace those that were lost. There has been considerable progress in understanding the molecular mechanisms of regeneration in non-mammalian vertebrates, and if this knowledge could be applied to humans, it might lead to the development of new types of regenerative therapies for patients with impaired vision. Five years ago, we discovered that by expressing a key proneural regulatory gene, called Ascl1, in the Muller glia of mice, we can induce them to regenerate new neurons after injury. The new regenerated neurons in the mouse retinas wired up with the existing, undamaged neurons and became functional. These results showed for the first time that functional neuron regeneration is possible in mammals, like ourselves; however, we have found that additional factors are likely required to guide the regeneration to the proper types and numbers of neurons needed to address specific diseases. In this proposal, our aim is to better define the specific transcription factor combinations that best regenerate each of the major retinal neurons types. We also propose to determine whether the types of neurons regenerated by the Muller glia are influenced by the type of retinal injury, and whether the process can be made efficient enough to restore functional vision in animal models of retinal degeneration. Lastly, we propose studies to better understand the signaling pathways that could be harnessed to further direct the MG-mediated regeneration process. At the end of five years, we expect to have further refined the potential for regeneration in the treatment of retinal disease and trauma.

抽象的目前，尚无有效的疗法来替代视网膜神经元丧失患者的退化神经元来自退化性疾病，例如在青光眼和黄斑变性的患者中发生。相比之下非哺乳动物脊椎动物（例如鱼类和两栖动物）的视网膜表现出强大的再生反应视网膜损伤后。视网膜受伤后，鱼穆勒胶质胶质产生了所有不同类型的视网膜神经元代替那些丢失的神经元。理解分子已经取得了很大进展非哺乳动物脊椎动物的再生机制，如果可以将这些知识应用于人类，这可能会导致视力受损的患者开发新型的再生疗法。五几年前，我们发现，通过在Muller Glia中表达一个称为ASCL1的关键胸膜调节基因小鼠，我们可以在受伤后诱使它们再生新的神经元。鼠标中的新再生神经元视网膜与现有的未损坏神经元连接起来，并起作用。这些结果显示了像我们自己一样，在哺乳动物中首次可能在功能性神经元再生。但是，我们发现可能需要其他因素来指导再生对神经元的适当类型和数量需要解决特定疾病。在此提案中，我们的目标是更好地定义特定的转录因子最能重生每种主要视网膜神经元类型的组合。我们还建议确定 Muller Glia再生的神经元的类型是否受到视网膜损伤类型的影响，是否可以使该过程有效地足以恢复视网膜动物模型中的功能视觉退化。最后，我们建议研究以更好地了解可以利用的信号通路进一步指导MG介导的再生过程。在五年结束时，我们预计会进一步完善了在视网膜疾病和创伤治疗中再生的潜力。