Transcriptional regulation of retinal cell differentiation and function

视网膜细胞分化和功能的转录调控

• 批准号: 8630327
• 负责人: Seth Blackshaw
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630327
• 关键词: Amacrine Cells; Automobile Driving; Biochemical; Candidate Disease Gene; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Clinical; Complement; DNA Binding; Data; Development; Disease; Down-Regulation; Electroporation; Gene Activation; Gene Expression; Genes; Genetic; Glial Differentiation; Gliosis; Hypertrophy; Hypothalamic structure; Individual; Injury; Mediating; Molecular; Natural regeneration; Neonatal; Neuroglia; Pattern; Photoreceptors; Play; Process; Regulation; Repression; Rest; Retina; Retinal; Retinal Dystrophy; Role; Signal Transduction; Source; Staging; Transcription Coactivator; Transcriptional Regulation; Work; base; cell type; cofactor; functional restoration; glial cell development; gliogenesis; homeodomain; in vivo; injured; insight; mRNA Expression; neurogenesis; neuroprotection; novel strategies; prevent; progenitor; programs; public health relevance; regenerative therapy; response to injury; retinal neuron; retinal progenitor cell; screening; selective expression; transcription factor; transdifferentiation

DESCRIPTION (provided by applicant): Retinal Muller glia play a critical role in regulating the survival of retinal neurons following damage, and may be a useful source for cell-based regenerative therapies for retinal dystrophies. Over the past few years, we have established the progenitor and glial-expressed homeodomain transcription factor Lhx2 as an essential regulator of multiple different aspects of Muller glial development and function. In neonatal retinal progenitors, Lhx2 promotes neurogenesis at the expense of gliogenesis, but Lhx2 is essential for glial differentiation when expressed in postmitotic glial precursors. Lhx2 also functions in terminally differentiated Muller glia to both repress expression of genes induced in hypertrophic gliosis and promote expression of glial-derived neuroprotective factors following injury. We aim to investigate the molecular mechanisms that allow Lhx2 to perform this diverse range of regulatory functions. We aim to comprehensively profile Lhx2 DNA binding patterns in retinal progenitors, glial precursors and in mature resting and reactive Muller glia. We will use this data together with mRNA expression data from these cell types to identify candidate cofactors that selectively and differentially regulate Lhx2 function, and confirm this using both in vivo electroporation and targeted genetic approaches. We ultimately intend to use these findings to determine if glial dedifferentiation can be induced, or the neuroprotective functions of retinal gla enhanced, by manipulating Lhx2 activity.

描述（由申请人提供）：视网膜Muller神经胶质细胞在调节损伤后视网膜神经元的存活中起关键作用，并且可能是视网膜营养不良的基于细胞的再生疗法的有用来源。在过去的几年中，我们已经建立了祖细胞和胶质表达的同源结构域转录因子Lhx2作为一个重要的调节多个不同方面的穆勒神经胶质细胞的发展和功能。在新生儿视网膜祖细胞中，Lhx2促进神经发生的代价是胶质细胞的生成，但Lhx2是必不可少的胶质细胞分化时，有丝分裂后的胶质细胞前体表达。Lhx2还在终末分化的Muller神经胶质中起作用，以抑制在肥大性神经胶质增生中诱导的基因表达，并促进损伤后神经胶质源性神经保护因子的表达。我们的目标是调查的分子机制，使Lhx2执行这一系列不同的监管职能。我们的目标是全面的配置文件Lhx2在视网膜祖细胞，神经胶质前体细胞和成熟的休息和反应穆勒神经胶质细胞的DNA结合模式。我们将使用这些数据 与来自这些细胞类型的mRNA表达数据一起鉴定选择性和差异性调节Lhx2功能的候选辅因子，并使用体内电穿孔和靶向遗传方法两者来证实这一点。我们最终打算利用这些发现来确定是否可以通过操纵Lhx2活性来诱导胶质细胞去分化，或者增强视网膜gla的神经保护功能。