The In Vivo Function of Id2 in Retinal Proliferation and Differentiation

Id2在视网膜增殖和分化中的体内功能

• 批准号: 7673715
• 负责人: Rosa A Uribe
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673715
• 关键词: Affect; Cancerous; Cell Count; Cell Culture Techniques; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Proliferation Regulation; Cell Survival; Cell division; Cells; Commit; Defect; Development; Developmental Process; Diagnostic Neoplasm Staging; Differentiation and Growth; Disease; Embryonic Eye; Event; Exhibits; Eye; Family; Fertilization; Goals; Growth; Helix-Turn-Helix Motifs; Human; Intrinsic factor; Knowledge; Learning; Light; Link; Location; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Microphthalmos; Molecular; Nature; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neuronal Differentiation; Neurons; Pathway interactions; Pattern; Phase; Play; Process; Property; Protein Family; Proteins; Regulation; Regulatory Pathway; Retina; Retinal; Retinoblastoma; Role; Series; Signal Pathway; Signal Transduction; Sonic Hedgehog Pathway; Testing; Time; Tissues; Undifferentiated; Zebrafish; blastomere structure; gain of function; human disease; in vivo; loss of function; nerve stem cell; neuroblast; neurogenesis; novel; relating to nervous system; research study; retinal neuron; retinal progenitor cell; retinogenesis; segregation; smoothened signaling pathway

DESCRIPTION (provided by applicant): The construction of the nervous system is an integrated series of developmental steps, commencing with the segregation of a small group of embryonic cells fated to become neural progenitors. These neural progenitors then remain proliferative and undifferentiated until they have become committed to distinct neural cell fate. As in most neural tissue, within the vertebrate retina, the cell and molecular strategies that cells use to control these processes remain poorly understood. Even worse, most forms of cancer exhibit distinctly misregulated control over these events, and the nature underlying many human diseases are tied to perturbations in these processes. Therefore, the overarching goal of this proposal is to enhance our understanding of the intracellular mechanisms governing neuroblast proliferation, lineage commitment and differentiation within the developing vertebrate retina. This will be accomplished by utilizing the zebrafish retina to understand the role of the intrinsic factor Id2 (Inhiibitor of Differentiation) in retinal development. The specific Aims of this proposal are 1. To determine the function of Id2 during zebrafish retinogenesis, 2. To determine the molecular mechanisms underlying Id2 function in the developing zebrafish retina, and 3. To determine if Id2 is regulated by the Sonic Hedgehog Pathway (Shh). These Aims will be accomplished using Id2 loss and gain-of-function strategies in vivo in order to define the functional role of Id2 during zebrafish retinogenesis, and Shh loss and gain-of-function methods will also be used to assess if Id2 is regulated by Shh in the developing vertebrate retina. The experiments in this proposal will shed light on how the intrinsic factor Id2 regulates growth and differentiation of the vertebrate eye, and how it's function may be controlled by mitogenic properties of the Shh signaling pathway. As the formation of many human neurological, developmental and cancerous diseases are linked to disruptions in such early developmental processes as cell division, cell specialization and cell survival, the purpose of this study is to enhance our understanding of how these processes normally occur at the molecular level within the cell, and how they are controlled over developmental time. Specifically, this study will examine how these events occur in the developing retina, thereby increasing our knowledge of how the retina forms, and providing clues to the events that may be disrupted in the early stages of cancer, such as retinoblastoma, as well as neurodegenerative diseases affecting the retina.

描述（由申请人提供）：神经系统的构建是一系列集成的发育步骤，从一小群注定会成为神经祖细胞的胚胎细胞的分离开始。然后，这些神经祖细胞保持增殖和未分化状态，直到它们决定了不同的神经细胞命运。与大多数神经组织一样，在脊椎动物视网膜内，细胞用来控制这些过程的细胞和分子策略仍然知之甚少。更糟糕的是，大多数形式的癌症对这些事件的控制明显失控，许多人类疾病的本质都与这些过程的扰动有关。因此，该提案的首要目标是增强我们对发育中的脊椎动物视网膜内控制神经母细胞增殖、谱系定型和分化的细胞内机制的理解。这将通过利用斑马鱼视网膜了解内在因子 Id2（分化抑制剂）在视网膜发育中的作用来实现。该提案的具体目标是 1. 确定 Id2 在斑马鱼视网膜发生过程中的功能，2. 确定发育中的斑马鱼视网膜中 Id2 功能的分子机制，以及 3. 确定 Id2 是否受 Sonic Hedgehog 通路调节（嘘）。这些目标将通过体内 Id2 丢失和功能获得策略来实现，以确定 Id2 在斑马鱼视网膜发生过程中的功能作用，Shh 丢失和功能获得方法也将用于评估 Id2 是否受到调节脊椎动物视网膜发育中的“嘘”现象。该提案中的实验将揭示内因子 Id2 如何调节脊椎动物眼睛的生长和分化，以及它的功能如何通过 Shh 信号通路的有丝分裂特性来控制。由于许多人类神经、发育和癌症疾病的形成与细胞分裂、细胞特化和细胞存活等早期发育过程的破坏有关，这项研究的目的是增强我们对这些过程如何在分子水平上正常发生的理解。细胞内的水平，以及它们在发育过程中如何受到控制。具体来说，这项研究将检查这些事件如何在发育中的视网膜中发生，从而增加我们对视网膜如何形成的了解，并为癌症早期阶段可能被破坏的事件提供线索，例如视网膜母细胞瘤以及神经退行性疾病影响视网膜的疾病。