In vivo analysis of the developing vertebrate retina

脊椎动物视网膜发育的体内分析

基本信息

批准号：
8511648
负责人：
Rachel O Wong
金额：
$ 33.02万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511648
关键词：
Ablation Age Animals Area Biological Models Birth Calcium Cell Death Cell Survival Cell division Cell physiology Cells Color Visions Commit Complex Congenital Abnormality Cytotoxin Defect Development Disease Ensure Environment Enzymes Eye Failure Funding Generations Genetic Genetic Models Goals Image Individual Injury Knowledge Learning Methods Modeling Natural regeneration Nervous System Physiology Neuraxis Neuronal Dysfunction Neurons Opsin Outcome Oxidoreductase Pathway interactions Pattern Photic Stimulation Photoreceptors Population Process Prodrugs Production Recruitment Activity Retina Retinal Retinal Cone Specificity Stem cells Structure Synapses Techniques Therapeutic Time Vision Visual system structure Zebrafish cell type design functional restoration in vivo in vivo Model injured insight model development mutant neuron development neuron loss novel postsynaptic precursor cell presynaptic promoter reconstruction regenerative regenerative therapy repaired stem cell therapy tool ultraviolet vision development

项目摘要

DESCRIPTION (provided by applicant): Neuronal loss and dysfunction can arise both during development due to congenital defects, and at maturity because of injury and disease. Failure to produce the correct cell types and their precise connectivity patterns have severe functional consequences. Thus, our broad goal is to advance our understanding of: (i) the cellular processes that ensure the proper generation of neurons and their circuits during development, and (ii) the processes that enable or limit neuronal populations from re-establishing their origina circuitry after injury or disease. Although stem-cell therapy represents a major strategy for restoring function, it is not yet known whether new neurons placed in injured or diseased cellular environments are able to form their original connectivity patterns. Because survival of cells seeded within the central nervous system remains challenging, we will take advantage of zebrafish, an important genetic model system for investigating development and disease, to achieve our goals. This is because zebrafish have an inherent ability to regenerate its neurons. We propose to focus on the first synapse in the visual system between cone photoreceptors and their target bipolar cells because structure, function and connectivity of these cell types are heavily studied, and perturbations to their connections result in impaired vision. We will use genetic tools and state-of-the-art imaging approaches to answer three outstanding questions in the fields of neuronal and visual development and repair. In Aim 1, we will determine whether there are endogenous cell-genesis pathways directed at producing and regenerating specific subtypes within a single neuronal type, the cone photoreceptors. In Aim 2, we will ascertain how postsynaptic bipolar cells compensate for the absence of a preferred presynaptic cone type during development, in models of congenital disease. In Aim 3, we will selectively ablate cone photoreceptors or bipolar cells in vivo and assess the specificity and accuracy of circuit reassembly upon neuronal regeneration. Together, our findings will significantly increase our understanding of the generative and regenerative processes that are recruited in vivo to establish complex circuits, such as the cone pathways, in development and in repair.

描述（由申请人提供）：由于先天性缺陷而发育期间，神经元丧失和功能障碍都可能出现，并且由于受伤和疾病而成熟。无法产生正确的细胞类型及其精确的连通性模式会带来严重的功能后果。因此，我们的广泛目标是提高我们对：（i）确保在发育过程中确保神经元及其电路的细胞过程，以及（ii）使神经元种群在受伤或疾病后重新建立其原始电路的过程。尽管Stem-Cell疗法是恢复功能的主要策略，但尚不清楚放置在受伤或患病的细胞环境中的新神经元是否能够形成其原始连通性模式。由于中枢神经系统中种子的细胞的存活仍然具有挑战性，因此我们将利用斑马鱼（斑马鱼（斑马鱼），这是一种研究发展和疾病的重要遗传模型系统，以实现我们的目标。这是因为斑马鱼具有再生神经元的固有能力。我们建议专注于锥形感受器及其目标双极细胞之间视觉系统中的第一个突触，因为这些细胞类型的结构，功能和连通性进行了大量研究，并且对其连接的扰动导致视力受损。我们将使用遗传工具和最先进的成像方法来回答神经元和视觉开发和修复领域的三个杰出问题。在AIM 1中，我们将确定是否有内源性细胞生成途径是针对单个神经元类型（锥形感受器）内产生和再生特定亚型的。在AIM 2中，我们将确定在先天性疾病模型中，突触后双极细胞如何弥补发育过程中首选的突触前锥类型的缺失。在AIM 3中，我们将在体内有选择地烧蚀锥锥光感受器或双极细胞，并评估神经元再生时电路重新组装的特异性和准确性。总之，我们的发现将大大提高我们对在体内募集的生成和再生过程的理解，以建立复杂的电路，例如锥形途径，在开发和维修中。