The role of the bHLH transcription factor NeuroD in regulating photoreceptor rege

bHLH转录因子NeuroD在调节光感受器调节中的作用

• 批准号: 8456379
• 负责人: Scott Michael Taylor
• 金额: $ 5.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456379
• 关键词: Address; Adult; Animal Model; Animals; Biological Models; Blindness; Cell Cycle; Cell Proliferation; Cell Transplants; Cells; Degenerative Disorder; Development; Disease; Embryo; Fishes; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Human; Individual; Knowledge; Lead; Light; Mediating; Molecular; Mus; Natural regeneration; Nervous system structure; Neurons; Outcome; Pathway interactions; Photoreceptors; Process; Regenerative Medicine; Research; Retina; Retinal Diseases; Rodent; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Vertebrates; Vision; Vision Disorders; Withdrawal; Work; Zebrafish; base; improved; neurogenesis; photoreceptor progenitor; progenitor; public health relevance; regenerative therapy; research study; retinal regeneration; stem; transcription factor

DESCRIPTION (provided by applicant): Photoreceptor degenerative diseases lead to permanent vision loss in humans. The development of regenerative therapies that restore vision in humans will require substantial advances to the current understanding of mechanisms of stem cell-based regeneration. The long-term goal of our research is to understand the molecular mechanisms that govern stem cell-based neuronal regeneration in the retina, using zebrafish as a model organism. A next step in achieving this goal, and the overall objective of the present research, is to discern the role of NeuroD in photoreceptor regeneration. This objective will be accomplished by testing the central hypothesis that NeuroD is a key molecule in signaling pathways that control photoreceptor regeneration. This hypothesis will be tested by accomplishing 2 specific aims. Specific Aim 1 will test the specific hypotheses that 1) NeuroD is required for photoreceptor progenitors to exit the cell cycle during photoreceptor regeneration and 2) NeuroD function is mediated via downstream genes that are essential for photoreceptor regeneration. This will be accomplished by comparing photoreceptor regeneration, cell proliferation, and expression of downstream genes in regenerating retinas between normal and NeuroD-deficient retinas. Specific Aim 2 will test the specific hypothesis that NeuroD mediates the function of canonical Wnt signaling in photoreceptor progenitors during photoreceptor regeneration. This will be accomplished by comparing neuroD expression and localization of the canonical Wnt effector (?-catenin), and determining the effects of canonical Wnt signaling manipulation on neuroD expression. This research will provide a significant and important step toward understanding pathways regulating photoreceptor regeneration in vertebrates, and will contribute to our fundamental knowledge of factors regulating stem cell-based regeneration in the nervous system. This contribution will provide critical information applicable to the development of regenerative therapies aimed at treating human retinal disease.

描述（由申请人提供）：光感受器退行性疾病导致人类永久视力丧失。恢复人类视力的再生疗法的发展将需要在当前对基于干细胞再生机制的理解中取得重大进展。我们研究的长期目标是了解视网膜中基于干细胞的神经元再生的分子机制，使用斑马鱼作为模型生物。实现这一目标的下一步以及本研究的总体目标是辨别神经轨道在光感受器再生中的作用。该目标将通过测试中心假设来实现，即神经轨道是控制光感受器再生的信号传导途径中的关键分子。该假设将通过实现2个具体目标来检验。特定的目标1将测试特定的假设，即1）神经落的光感受器祖细胞在光感受器再生过程中退出细胞周期和2）神经胶功能是通过下游基因介导的，这对于光感受器再生至关重要。这将通过比较受感受器的再生，细胞增殖和下游基因在正常和神经缺陷视网膜之间再生视网膜中的表达来实现。具体目标2将测试特定的假设，即神经轨道介导光感受器再生过程中光感受器祖细胞中规范Wnt信号的功能。这将通过比较规范Wnt效应子（？ - catenin）的神经趋势表达和定位来实现，并确定规范Wnt信号操纵对Neurod表达的影响。这项研究将为理解调节脊椎动物的光感受器再生的途径提供重要而重要的步骤，并将有助于我们对调节神经系统中基于干细胞再生的因素的基本知识。这项贡献将提供适用于旨在治疗人类视网膜疾病的再生疗法发展的关键信息。