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Regulation of interneuron formation in the developing retina

视网膜发育中中间神经元形成的调节

基本信息

批准号：
10295556
负责人：
DAVID L TURNER
金额：
$ 34.12万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295556
关键词：
Amacrine Cells Binding Proteins Binding Sites Biological Assay Biology Birth Blindness CRISPR/Cas technology Cell Differentiation process Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Binding Data Development Developmental Process Ectopic Expression Embryonic Development Eye Family Gene Expression Profile Gene Expression Regulation Generations Genes Genetic Transcription Genomics Goals Health Health Care Costs Human Individual Inherited Injury Interneurons Intervention Knowledge Lead Link Mammals Mediating Messenger RNA Methodology MicroRNAs Molecular Mus Natural regeneration Neural Crest Neuraxis Neurons Pathway interactions Patients Proteins Quality of life RNA Interference Regulation Reporter Reporting Repression Retina Retinal Diseases Role Site Structure Testing Tissues Transcription Coactivator Transcription Repressor Variant Visual Perception Visual impairment Work cell determination cell type cholinergic economic cost gene therapy genetic variant insight mRNA Expression novel strategies overexpression repair strategy repaired retinal regeneration retinogenesis stem cell biology stem cells transcription factor transcriptome sequencing

项目摘要

Abstract/Project Summary Retinal disease or injury leading to impaired vision or blindness are human health problems that reduce quality of life, generating significant human and economic costs. Advances in gene therapy and stem cell biology have made retinal repair a feasible goal. Nonetheless, rational repair strategies are constrained by current knowledge of retinal biology and development. The complex cellular composition of the retina, like other parts of the mammalian central nervous system, is an essential component of the retina’s functional capabilities, yet remains incompletely understood. The mammalian retina includes more than 100 distinct types of neurons. The generation of this cellular diversity during retinal development depends in part on sequential cascades of transcriptional regulators as well as other factors. We found the miR-216b microRNA can influence retinal development including the formation of amacrine and bipolar interneurons. We identified a target gene for this microRNA, a transcriptional repressor in the forkhead family, Foxn3, that when inhibited using RNAi or CRISPR in the developing retina increases amacrine cell formation, and when overexpressed reduces amacrine cell formation. The target genes of Foxn3 during retinal development are not known. Here we propose to identify mRNAs regulated by either loss or gain of Foxn3 function in the developing retina. We will analyze changes in mRNA expression to identify the molecular pathways by which Foxn3 modulates retinal cell fate decisions. In addition, we will identify genomic sites at which the Foxn3 protein binds in the developing retina to find candidate target genes. We also propose to analyze retinal development in the absence of miR- 216b or the related miR-216a microRNA, to determine if these miRNAs are required for amacrine cell differentiation or other functions, and to assess the function of two miR-216a/b genetic variants that may be linked to retinal disease. These studies will provide new insights into the regulation of development and cell determination in the mammalian retina. They are expected to provide information that may be relevant to retinal disease and that may contribute to new strategies to repair retinal tissue.

抽象/项目总结