Small heat shock proteins and retinotectal development

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扰动的影响。事实上，一些视觉系统障碍是由发育过程中出现的异常连接引起的，而且，像其他神经系统疾病一样，许多疾病可能既有遗传原因，也有环境原因。然而，不同的人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。是什么决定了应激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外，热休克蛋白(HSPs)还可以缓冲细胞免受环境胁迫的影响，如高温、紫外线、缺血、酒精和重金属毒性，以及遗传背景的突变。因此，热休克蛋白功能的缺陷往往会导致对环境或遗传应激源的敏感性增加。小分子热休克蛋白(SHSP)不仅可以保护发育中的视网膜投影免受应激源的伤害，而且可以调节正常的发育。这项提议的目标是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有几个优势，在其他脊椎动物系统中，这可能是非常耗时和资源密集型的。以下目标将阐述sHSPs在从视网膜到高级视觉中心的投射发育过程中的功能： 目的I.克隆和鉴定斑马鱼sHSPs的发育和应激诱导表达。 Aim Il.确定sHSPs是否调节体内视网膜神经节细胞(RGC)的生长锥体。 目的III.确定是否需要sHSP来保护和/或从应激源中恢复。 这将是第一次系统地描述sHSP的胚胎功能，无论是在视觉系统的轴突引导过程中还是在一般情况下。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方面的实质性进展。

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.