Cell-Cell Signaling in Visual Development

视觉发育中的细胞间信号传导

• 批准号: 7689731
• 负责人: John G Flanagan
• 金额: $ 42.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689731
• 关键词: Alkaline Phosphatase; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Axon; Binding; Binding Sites; Biochemical; Biological; Biological Models; Biological Process; Biology; Brain; Branchiostoma floridae AmphiEn protein; Cell surface; Chimeric Proteins; Cues; Development; Diffusion; Disease; Embryo; Eph Family Receptors; Ephrins; Eye; FGF8 gene; Family; Goals; Grant; Growth; Growth Cones; Growth and Development function; Imaging Techniques; Knowledge; Label; Lead; Ligands; Location; Maintenance; Maps; Messenger RNA; Methods; Midbrain structure; Molecular; Natural regeneration; Neuron-Glia Cell Adhesion Molecules; Pathology; Play; Production; Protein Biosynthesis; Proteins; RNA; RNA Decay; Regulation; Research Personnel; Resources; Retina; Retinal Ganglion Cells; Role; Signal Transduction; Signaling Molecule; Site; System; Tectum Mesencephali; Therapeutic Agents; Translations; Visual; Visual system structure; Work; amyloid precursor protein processing; axon growth; axon guidance; base; contactin; experience; extracellular; field study; improved; intercellular communication; interest; member; novel; receptor; relating to nervous system; repaired; response; retinal axon; retinotectal; retinotopic; superior colliculus Corpora quadrigemina; therapeutic target; vision development

DESCRIPTION (provided by applicant): Correct functioning of the visual system requires axonal connections from eye to brain to develop with precisely-defined spatial order. The broad long-term objective of our studies is to identify cell-cell signaling molecules, and characterize their functions and mechanisms of action in guiding the precise development of visual axonal connections. The proposal focuses on retinal ganglion cell axons, and their projections to the tectum, a retinal axon target which has long been a major model system. Aim 1 proposes to study novel molecular interactions in the retinotectal system. The Amyloid Precursor Protein (APP) is a cell surface molecule with important roles in Alzheimer's pathology, but its normal functions are not well understood. APP has long been proposed to act as a cell surface ligand or receptor. In preliminary studies, binding partners for APP have been identified and are prominently expressed in the retinotectal system. Studies will be continued into the molecular interactions of these proteins, and their effects on APP signaling and retinal axon growth and development. Aim 2 is to study mechanisms of tectal gradient formation. Ephrins are known to act as graded positional labels for axon mapping in the tectum. However, the mechanisms that initially set up these gradients are not well understood. Studies will be continued to identify the steps in the upstream molecular hierarchy that initially convert a non-graded to a graded distribution, and to identify biochemical mechanisms for gradient formation in the tectum. Aim 3 is to characterize RNA-based mechanisms for regulation in retinal axons. Evidence has accumulated to show that regulated protein synthesis occurs within axons and can have important functions. This has opened up an exciting new field of study, but the mechanisms remain poorly characterized. RNA-based regulation mechanisms will be studied in retinal ganglion cell axons, including the location and dynamics of synthesis, and mechanisms for regulated translation of mRNAs in response to extracellular cues. While our primary goal is to elucidate basic molecular mechanisms, the work has broader implications for disease. APP is important for its roles in Alzheimer's disease, including pathology of the retina. Identification of ligands that regulate APP processing may lead to therapeutic targets to inhibit production of beta amyloid. More generally, studies to identify and characterize novel cell-cell signaling cues in the visual system, may lead to therapeutic agents for maintenance, repair or regeneration of visual connections.

描述（由申请人提供）：视觉系统的正确功能需要从眼睛到大脑的轴突连接以精确定义的空间顺序发育。我们研究的广泛的长期目标是识别细胞-细胞信号分子，并表征它们在指导视觉轴突连接精确发育中的功能和作用机制。该提案的重点是视网膜神经节细胞轴突，以及它们向顶盖的投射，顶盖是长期以来一直是主要模型系统的视网膜轴突靶点。目的1研究视网膜顶盖系统中的新型分子间相互作用。淀粉样前体蛋白（APP）是一种细胞表面分子，在阿尔茨海默病的病理学中具有重要作用，但其正常功能尚不清楚。APP长期以来被认为是细胞表面的配体或受体。在初步研究中，APP的结合伙伴已被确定，并在视网膜顶盖系统中显着表达。研究将继续进入这些蛋白质的分子相互作用，以及它们对APP信号传导和视网膜轴突生长和发育的影响。目的二是研究顶盖梯度的形成机制。已知肝配蛋白充当顶盖中轴突映射的分级位置标签。然而，最初建立这些梯度的机制还没有得到很好的理解。研究将继续确定的步骤，在上游的分子层次结构，最初转换为一个分级的非分级分布，并确定在顶盖梯度形成的生化机制。目的3是表征基于RNA的视网膜轴突调控机制。越来越多的证据表明，受调节的蛋白质合成发生在轴突内，并具有重要的功能。这开辟了一个令人兴奋的新研究领域，但其机制仍然缺乏特征。将在视网膜神经节细胞轴突中研究基于RNA的调节机制，包括合成的位置和动力学，以及响应细胞外线索的mRNA调节翻译的机制。虽然我们的主要目标是阐明基本的分子机制，但这项工作对疾病有更广泛的意义。APP在阿尔茨海默病中的作用很重要，包括视网膜的病理学。鉴定调节APP加工的配体可能导致抑制β淀粉样蛋白产生的治疗靶点。更一般地，识别和表征视觉系统中新的细胞-细胞信号传导线索的研究可能导致用于维持、修复或再生视觉连接的治疗剂。