Cell-Cell Signaling in Visual Development

描述（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展。我们研究的长期目标是识别细胞-细胞信号分子，并表征其功能和作用机制，以指导视觉轴突连接的精确发展。本研究的重点是视网膜神经节细胞轴突及其向顶盖的投射，顶盖是视网膜轴突的靶点，长期以来一直是主要的模型系统。目的1提出研究视网膜系统中新的分子相互作用。淀粉样前体蛋白（APP）是一种在阿尔茨海默病病理过程中起重要作用的细胞表面分子，但其正常功能尚不清楚。APP很早就被认为是一种细胞表面配体或受体。在初步研究中，APP的结合伙伴已被确定，并在视网膜系统中显著表达。我们将继续研究这些蛋白的分子相互作用，以及它们对APP信号和视网膜轴突生长发育的影响。目的二是研究顶角梯度的形成机制。ephrin被认为是顶盖轴突定位的分级标签。然而，最初建立这些梯度的机制还没有得到很好的理解。研究将继续确定上游分子层次中的步骤，这些步骤最初将非梯度分布转化为梯度分布，并确定在顶盖中梯度形成的生化机制。目的3是表征基于rna的视网膜轴突调节机制。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，但其机制仍不清楚。我们将研究视网膜神经节细胞轴突中基于rna的调控机制，包括合成的位置和动力学，以及响应细胞外信号的mrna调控翻译的机制。虽然我们的主要目标是阐明基本的分子机制，但这项工作对疾病具有更广泛的意义。APP在阿尔茨海默病中发挥重要作用，包括视网膜病理。识别调节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。更广泛地说，识别和表征视觉系统中新的细胞-细胞信号信号的研究，可能会导致维持、修复或再生视觉连接的治疗药物。

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.