Cytoskeletal regulation and Yap/Taz activity in differentiating retinal neurons

分化视网膜神经元中的细胞骨架调节和 Yap/Taz 活性

• 批准号: 9788450
• 负责人: Steven J Henle
• 金额: $ 24.85万
• 依托单位: CARTHAGE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788450
• 关键词: Address; Adhesions; Adult; Apical; Architecture; Back; Biological Assay; Biological Models; Blindness; Cell Differentiation process; Cell Nucleus; Cell division; Cells; Complement; Cytoskeleton; Defect; Development; Elements; Engineering; Feedback; Gatekeeping; Genetic Transcription; Goals; Human; Imaging Techniques; Injury; Knock-out; Knowledge; Lead; Link; Molecular; Molecular Genetics; Morphology; Mus; Mutation; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neuronal Differentiation; Neurons; Phase; Play; Process; Proteins; Regulation; Research; Retina; Retinal; Retinal Ganglion Cells; Role; Series; Side; Signal Pathway; Structural Protein; Structure; Surface; Systems Development; Technical Expertise; Techniques; Testing; Training; Transcriptional Activation; Transcriptional Regulation; Work; Zebrafish; cell type; experimental study; genetic manipulation; genetic regulatory protein; in vivo; in vivo imaging; innovation; insight; neurogenesis; neuron development; novel; prevent; progenitor; protein structure; regenerative; regenerative therapy; repaired; retinal neuron; retinal progenitor cell; retinal regeneration; skills; tool; tool development

PROJECT SUMMARY / ABSTRACT The human retina does not regenerate after injury. This proposal examines retinal development to better understand the molecular mechanisms that could be used to initiate regeneration. Developing neurons must precisely regulate cytoskeletal dynamics to establish their unique morphology that is required for proper function. It is not well understood how cytoskeletal dynamics change across development and after injury in vivo. Yes Associated Protein (YAP) and Tafazzin (TAZ) are functionally similar proteins that are critical for maintaining the progenitor state through transcriptional regulation. Mutations to YAP/TAZ result in retinal lamination defects through an unknown mechanism. Additionally, unlike other retinal neurons, retinal ganglion cells continue to express YAP/TAZ after development. Intriguingly, cytoskeletal tension can inhibit YAP/TAZ activity and YAP/TAZ can regulate cytoskeletal dynamics. This creates an unusual molecular feedback loop between structural proteins and transcriptional regulators. The overall goal of this proposal is to understand the molecular mechanisms by which the cytoskeleton and YAP/TAZ coordinate retinal development, and the role they play in retinal regeneration. The central hypothesis is that cytoskeletal rearrangements required for retinal differentiation downregulate YAP/TAZ activity and thus drive cells out of the progenitor state. With the knowledge gained from these studies, the ultimate goal is to reverse engineer this process in adult cells, so we can then drive cells to a state of enhanced regenerative potential. To this end I will use a combination of innovative in vivo imaging techniques, genetic manipulations, and regeneration assays to better understand the molecular mechanisms by which the cytoskeleton and YAP/TAZ orchestrate retinal development and regeneration. The initial experiments in this proposal will focus on developing tools and techniques in zebrafish to investigate the cytoskeleton in order to test the overall hypothesis. Mastery of the zebrafish model system is a key element of the training potential of the K99 phase, and will complement my previous work examining retinal development in mice. Having technical expertise in both mouse and zebrafish will enable me to answer the most critical questions by having experimental access across retinal development, and a wide range of molecular and genetic tools. Taken together this training plan will empower me to develop an independent line of research that can significantly contribute to the development of regenerative therapies for the retina, and ultimately prevent vision loss.

项目摘要/摘要