Small heat shock proteins and retinotectal development

小热休克蛋白和视网膜顶盖发育

• 批准号: 6710463
• 负责人: Lara Diane Hutson
• 金额: $ 16.5万
• 依托单位: WILLIAMS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710463
• 关键词: axon; confocal scanning microscopy; developmental neurobiology; environmental stressor; genetic models; heat shock proteins; in situ hybridization; neuronal guidance; retinal ganglion; vision; zebrafish

DESCRIPTION (provided by applicant): It is widely recognized that the developing nervous system is particularly vulnerable to the effects of genetic or environmental perturbation. Indeed, several visual system disorders arise from abnormal wiring that occurs during development, and, like other neurological disorders, many are likely to have both genetic and environmental etiology. However, responses to stressors vary widely between individuals, making it difficult to associate a disease with its environmental trigger. What determines when a stressor will have catastrophic consequences to the developing embryo is poorly understood. However, in addition to regulating a variety of normal physiological processes, heat shock proteins (HSPs) buffer cells from the effects of environmental insult, such as elevated temperature, UV light, ischemia, alcohol, and heavy metal toxicity, as well as mutations in the genetic background. Therefore, defects in HSP function frequently result in increased sensitivity to environmental or genetic stressors. Small HSPs (sHSPs) are good candidates for not only protecting the developing retinal projection from stressors but also regulating normal development. The goal of this proposal is to test these possibilities using the zebrafish as a model system. The zebrafish has several advantages for analyzing the in vivo functions of candidate genes, which can be prohibitively time- and resource-intensive in other vertebrate systems. The following aims will address the function of sHSPs during development of the projection from the retina to higher visual centers: Aim I. Clone and characterize the developmental and stress-induced expression of sHSPs in zebrafish. Aim Il. Determine whether sHSPs regulate retinal ganglion cell (RGC) growth cones in vivo. Aim III. Determine whether sHSPs are required for protection and/or recovery from stressors. This will be the first systematic characterization of the embryonic functions of sHSPs, both generally and in the process of axon guidance in the visual system. The results of these studies could lead to both substantial advances in our understanding of visual system development and strategies to prevent and treat visual disorders.

描述（由申请人提供）：人们普遍认为，发育中的神经系统特别容易受到遗传或环境干扰的影响。事实上，一些视觉系统疾病是由发育过程中发生的异常布线引起的，并且像其他神经系统疾病一样，许多可能具有遗传和环境病因。然而，个体对压力源的反应差异很大，因此很难将疾病与其环境触发因素联系起来。是什么决定了压力源何时会对发育中的胚胎产生灾难性的后果，人们对此知之甚少。然而，除了调节各种正常的生理过程之外，热休克蛋白（HSP）还缓冲细胞免受环境损伤的影响，例如升高的温度，紫外线，缺血，酒精和重金属毒性，以及遗传背景中的突变。因此，HSP功能的缺陷经常导致对环境或遗传应激源的敏感性增加。小热休克蛋白（sHSPs）不仅可以保护发育中的视网膜投射免受应激源的影响，而且还可以调节正常发育。 这项提案的目的是使用斑马鱼作为模型系统来测试这些可能性。斑马鱼在分析候选基因的体内功能方面具有几个优势，这在其他脊椎动物系统中可能是令人望而却步的时间和资源密集型。以下目标将解决sHSP在从视网膜到高级视觉中心的投射发育期间的功能： 艾姆岛斑马鱼sHSPs基因的克隆及发育和应激诱导表达的研究 艾姆岛确定sHSPs是否在体内调节视网膜神经节细胞（RGC）生长锥。 Aim III.确定是否需要sHSP来保护和/或从压力源中恢复。 这将是第一个系统的表征sHSPs的胚胎功能，无论是一般的视觉系统中的轴突指导的过程中。这些研究的结果可能会导致我们对视觉系统发育的理解以及预防和治疗视觉障碍的策略取得实质性进展。