Neurogenesis at the mammalian retinal-ciliary margin

哺乳动物视网膜睫状体边缘的神经发生

• 批准号: 7527571
• 负责人: STEVEN W WANG
• 金额: $ 37.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527571
• 关键词: Adult; Amacrine Cells; Birth; Cell Differentiation process; Cell Proliferation; Cells; Code; Competence; Data; Disease; Engineered Gene; Ensure; Exhibits; Eye diseases; Gene Delivery; Gene Targeting; Generations; Genes; Genetic Engineering; Glaucoma; Human; Intrinsic factor; Lead; Light; Molecular; Mus; Natural regeneration; Neurons; Norrie' s disease; Outcome; Phase; Play; Preparation; Production; Property; Regulation; Reporting; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Scheme; Stem cells; Subfamily lentivirinae; Technology; Testing; Time; Vertebrates; Vision; adult stem cell; base; cell fate specification; cell type; design; horizontal cell; in vivo; insight; neurogenesis; optic nerve disorder; prenatal; public health relevance; research study; response; retinal damage; retinal neuron; retinal progenitor cell; retinogenesis; stem cell therapy; therapy design; tool; transcription factor

DESCRIPTION (provided by applicant): The long term objective of this proposal is to gain insights into the neuron generation potential of the mammalian retinal-ciliary margin as well as the molecular and cellular properties of cells within. This has important implications for the regeneration of functional neurons in damaged retinas. The proposal focuses on the retinal ganglion cell (RGC) forming competency of cells at the retinal-ciliary margin. RGCs play an essential role in visual function. Abnormalities in RGCs lead to major eye diseases in humans including glaucoma, Norrie disease, and other optic neuropathies. Stem cell administration, including supplementary of healthy retinal stem cells and in vivo activation of potential retinal stem cells, raises the hope for treating these diseases. However, isolated adult stem cells from the ciliary margin have limited differentiation potential; they do not give rise to RGCs and other "early" retinal cell types. The molecular and cellular mechanism negatively regulating RGC formation at the mammalian retinal-ciliary margin remains largely unknown. Recent advances in mouse genetic engineering and gene delivery technologies have provided new tools for exploring properties of the retinal-ciliary margin. This application will explore the molecular and cellular properties of the retinal-ciliary margin. Based on the hypothesis that cells in the retinal margin can retain their RGC forming competency for a latent period of time but eventually lose such a potential, three specific aims are proposed: 1) Determine how long can the mammalian retinal-ciliary margin retain its potential of forming new neurons. 2) Determine whether RGCs can be produced if new neuron is generated. 3) Determine whether RGCs, the first born retinal cell type, can be produced from the adult ciliary margin when minimal cell-intrinsic factors are supplied. Proposed experiments will take advantage of the advanced conditional gene targeting strategy and genetic engineered mouse lines generated during our past studies in quest of molecular mechanism in RGC formation. Results of these experiments will allow us to determine the state of competency of the ciliary margin cells at any given time. The results will also shed light into the regulation mechanism at mammalian retinal margin and provide information for designing treatments to cell degeneration related retinal diseases. PUBLIC HEALTH RELEVANCE: The proposed project studies cellular and molecular properties in the mammalian retinal margin. The result of this study will provide valuable information on utilizing cells from the retinal margin to replenish diseased or damaged retina.

描述(由申请人提供)：这项建议的长期目标是深入了解哺乳动物视网膜-纤毛边缘的神经元生成潜力以及其中细胞的分子和细胞特性。这对受损视网膜中功能神经元的再生具有重要意义。该提案侧重于视网膜-睫状缘细胞的视网膜神经节细胞(RGC)的形成能力。视网膜节细胞在视觉功能中起着至关重要的作用。视网膜节细胞的异常会导致人类的主要眼病，包括青光眼、诺里病和其他视神经疾病。干细胞的应用，包括补充健康的视网膜干细胞和体内激活潜在的视网膜干细胞，为治疗这些疾病带来了希望。然而，从睫毛边缘分离的成体干细胞分化潜力有限；它们不能产生RGC和其他“早期”视网膜细胞类型。负调控哺乳动物视网膜-睫状缘RGC形成的分子和细胞机制在很大程度上仍不清楚。小鼠基因工程和基因传递技术的最新进展为探索视网膜-纤毛边缘的特性提供了新的工具。这项应用将探索视网膜-睫状缘的分子和细胞特性。基于视网膜边缘的细胞可以在一段潜在的时间内保持其RGC形成能力，但最终失去这种能力的假设，提出了三个具体的目标：1)确定哺乳动物的视网膜-纤毛边缘可以保持多久的形成新神经元的潜力。2)确定如果有新的神经元产生，是否可以产生RGC。3)确定最早出生的视网膜细胞类型--视网膜神经节细胞是否可以在提供最少的细胞内在因素的情况下从成体睫状缘产生。拟议的实验将利用我们在过去的研究中产生的先进的条件基因打靶策略和基因工程小鼠系，以探索RGC形成的分子机制。这些实验的结果将使我们能够确定睫状缘细胞在任何给定时间的能力状态。这些结果也将有助于揭示哺乳动物视网膜边缘的调节机制，并为设计治疗与细胞变性相关的视网膜疾病提供信息。公共卫生相关性：拟议的项目研究哺乳动物视网膜边缘的细胞和分子特性。这项研究的结果将为利用视网膜边缘细胞来补充病变或受损的视网膜提供有价值的信息。