Neuronal Development, Injury and Repair in the Retina

视网膜神经元发育、损伤和修复

• 批准号: 8123244
• 负责人: Peter F Hitchcock
• 金额: $ 51.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123244
• 关键词: Adult; Biology; Birth; Blindness; Brain; Cell Cycle; Cell Transplants; Cells; Cessation of life; Data; Development; Disease; Event; Extracellular Matrix; Fishes; Funding; Genetic; Goals; Growth Factor; Growth Factor Gene; Health; Human; Injury; Knowledge; Literature; Mediating; Microglia; Mitotic; Molecular; Natural regeneration; Nerve Tissue; Nervous system structure; Neuraxis; Neurons; Outcome; Pathway interactions; Photoreceptors; Play; Progranulin; Regulation; Research; Retina; Retinal; Role; Signal Transduction; Signaling Molecule; Source; Stem cells; Testing; Therapeutic Uses; Tissues; Transplantation; Vision; Withdrawal; Work; Zebrafish; adult stem cell; base; cell type; driving force; injured; injury and repair; killings; knowledge of results; midkine; nerve stem cell; neural circuit; neurogenesis; neuron development; photoreceptor progenitor; progenitor; programs; public health relevance; receptor; regenerative; relating to nervous system; repaired; retinal neuron; stem; teleost; transcription factor

DESCRIPTION (provided by applicant): Injuries or diseases that kill retinal neurons and receptors block vision at it source. The resulting blindness is permanent. The inability to repair in the retina is a hallmark of the human central nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The long-term objective of this project is to elucidate the mechanisms that regulate the birth, death and regeneration of neurons and photoreceptors in the vertebrate retina. This program of research utilizes the zebrafish, because the fish retina is the only vertebrate CNS tissue where intrinsic stem cells can regenerate a single neuronal type that integrates into an existing circuit or can regenerate all cell types that completely restore the original tissue. Thus, investigating stem cell-based neuronal and photoreceptor regeneration in the teleost retina will advance our knowledge of mechanisms that govern the ability of intrinsic stem and progenitor cells to restore neural circuits in the injured brain. The resulting knowledge will guide the therapeutic use of transplanted stem and progenitor cells to treat retinal injuries, blindness and disease. Three Specific Aims are proposed, each directed toward revealing mechanisms that regulate the genesis and regeneration of photoreceptors. Specific Aim 1 will investigate the function of the bHLH transcription factor, NeuroD, in both the developing and regenerating retina. Specific Aim 2 will test the hypothesis that microglia play a neurogenic role during photoreceptor regeneration. Specific aim 3 will test the hypothesis that the soluble growth factor, midkine-a, controls aspects of retinal development in larval zebrafish and photoreceptor regeneration in adults. Together these specific aims represent a focused and integrated research program to test specific hypotheses of the biology and regulation of retinal development and neuronal regeneration in the vertebrate nervous system. PUBLIC HEALTH RELEVANCE: Photoreceptors initiate the first step in vision, and in the human retina the death of photoreceptors leads to permanent blindness. The Specific Aims described in this proposal will investigate the mechanisms by which intrinsic stem and progenitor cells regenerate photoreceptors in an adult retina. This work is highly relevant to human health, because it explores the molecular mechanisms employed by adult stem cells to repair the retina and brain and will provide information relevant to the therapeutic use of neural stem and progenitor cells in humans.

描述（由申请人提供）：杀死视网膜神经元和受体的损伤或疾病会从根源上阻碍视力。由此造成的失明是永久性的。视网膜无法修复是人类中枢神经系统的一个标志。死亡的神经元不会被替换，失去的功能也不会恢复。这种惨淡的结果是神经干细胞和再生生物学领域研究的驱动力。该项目的长期目标是阐明调节脊椎动物视网膜中神经元和光感受器的出生、死亡和再生的机制。该研究计划利用斑马鱼，因为鱼的视网膜是唯一的脊椎动物中枢神经系统组织，其中内在干细胞可以再生单个神经元类型，整合到现有的回路中，或者可以再生完全恢复原始组织的所有细胞类型。因此，研究硬骨鱼视网膜中基于干细胞的神经元和光感受器再生将增进我们对控制内在干细胞和祖细胞恢复受损大脑神经回路能力的机制的了解。由此产生的知识将指导移植干细胞和祖细胞的治疗用途，以治疗视网膜损伤、失明和疾病。提出了三个具体目标，每个目标都旨在揭示调节光感受器发生和再生的机制。具体目标 1 将研究 bHLH 转录因子 NeuroD 在视网膜发育和再生中的功能。具体目标 2 将检验小胶质细胞在光感受器再生过程中发挥神经源性作用的假设。具体目标 3 将检验以下假设：可溶性生长因子中期因子-a 控制斑马鱼幼虫视网膜发育和成年斑马鱼感光器再生的各个方面。这些具体目标共同代表了一个重点突出的综合研究计划，以测试脊椎动物神经系统中视网膜发育和神经元再生的生物学和调节的具体假设。 公共健康相关性：光感受器启动了视觉的第一步，在人类视网膜中，光感受器的死亡会导致永久性失明。该提案中描述的具体目标将研究内在干细胞和祖细胞在成人视网膜中再生感光器的机制。这项工作与人类健康高度相关，因为它探索了成体干细胞修复视网膜和大脑的分子机制，并将提供与人类神经干细胞和祖细胞的治疗用途相关的信息。