Neurogenesis at the mammalian retinal-ciliary margin

描述（由申请人提供）：本提案的长期目标是深入了解哺乳动物视网膜-睫状体边缘的神经元生成潜力以及细胞的分子和细胞特性。这对受损视网膜功能神经元的再生具有重要意义。本研究的重点是视网膜神经节细胞（RGC）在视网膜睫状体边缘形成细胞的能力。rgc在视觉功能中起着至关重要的作用。RGCs的异常导致人类主要眼病，包括青光眼、诺里病和其他视神经病变。干细胞管理，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，增加了治疗这些疾病的希望。然而，从睫状体缘分离的成体干细胞分化潜力有限；它们不会产生RGCs和其他“早期”视网膜细胞类型。哺乳动物视网膜-睫状缘负性调控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睫状体缘的特性提供了新的工具。本应用程序将探索视网膜睫状体缘的分子和细胞特性。基于视网膜边缘细胞可在一段潜伏期内保持RGC形成能力，但最终会丧失这种能力的假设，本文提出了三个具体目标：1)确定哺乳动物视网膜-睫状缘形成新神经元的潜力可保持多长时间。2)如果产生新的神经元，判断是否可以产生RGCs。3)确定在提供最小细胞内在因子的情况下，成人睫状体缘能否产生第一种先天性视网膜细胞RGCs。我们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靶向策略和基因工程小鼠系来探索RGC形成的分子机制。这些实验的结果将使我们能够在任何给定的时间确定纤毛边缘细胞的能力状态。研究结果还将揭示哺乳动物视网膜边缘的调节机制，为设计细胞变性相关视网膜疾病的治疗方法提供信息。公共卫生相关性：拟建项目研究哺乳动物视网膜边缘的细胞和分子特性。本研究结果将为利用视网膜边缘细胞来补充病变或受损视网膜提供有价值的信息。

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.