Emerging imaging technologies for automated analyses of calcineurin-dependent brain function

项目摘要 钙调神经磷酸酶是一种具有广泛临床意义的磷酸酶。钙调神经磷酸酶抑制剂被用作 预防器官移植排斥反应的免疫抑制剂和钙调神经磷酸酶信号被认为在 在唐氏综合症和阿尔茨海默病中的关键作用。然而，人们对其影响知之甚少。 大脑中的钙调神经磷酸酶信号。动物模型系统是可用的，但神经系统的变化 在研究像大脑这样复杂的器官时，网络很容易被忽略。行为分析提供了一种 潜在的解决方案，因为可以检测到大脑结构和功能的细微变化。该中心的实验室 首席研究员开发了一种用于自动分析斑马鱼幼体行为的成像系统。 这种成像系统可以测量幼虫对微孔板中运动视觉刺激的反应，而不是 使用商用成像系统是可能的。该成像系统的能力将进一步 扩展了对384井格式的复杂行为的自动化分析。该项目由 中心假设，用于高通量分析脊椎动物行为的新成像技术将 有助于发现治疗神经功能障碍的新疗法。这一假设将在三年内得到检验 明确的目标。第一个目标是优化成像技术，以便高通量地分析复杂的 行为。第二个目标是使用优化的技术来成像钙调神经磷酸酶依赖的行为。 第三个目标是筛选钙调神经磷酸酶相关神经功能障碍的新治疗方法。总体而言，成功 完成这些目标将扩展对复杂行为进行高通量分析的方法， 提供更好的对大脑中钙调神经磷酸酶信号的基本理解，并有助于设计新颖的 钙调神经磷酸酶相关神经功能障碍的治疗。项目将受益于充满活力和合议性的 布朗大学的研究环境。首席调查员的主要任命是在 分子生物学、细胞生物学和生物化学系，是卡尼大学的教员 脑科学研究所和预测生物学发展中心。该部门提供以下方面的专业知识 发育生物学和细胞信号传递，这两个中心为 行为神经科学研究和信号网络的高内容成像分析 技术。

Project Summary Calcineurin is a phosphatase with broad clinical significance. Calcineurin inhibitors are used as immunosuppressants to prevent rejection of organ transplants and calcineurin signaling is thought to play a critical role in Down syndrome and Alzheimer’s disease. However, very little is known about the effects of modulated calcineurin signaling in the brain. Animal model systems are available, but changes in neural networks are easily missed when studying an organ as complex as the brain. Analyses of behavior offer a potential solution, since subtle changes in brain structure and function can be detected. The laboratory of the principal investigator developed an imaging system for automated analyses of behavior in zebrafish larvae. This imaging system can measure larval responses to moving visual stimuli in microplates, which is not possible with commercially-available imaging systems. The capabilities of this imaging system will be further expanded for automated analyses of complex behaviors in a 384-well format. The project is guided by the central hypothesis that novel imaging technologies for high-throughput analyses of vertebrate behavior will contribute to the discovery of novel treatments for neural dysfunction. This hypothesis will be tested in three specific aims. The first aim is to optimize imaging technologies for high-throughput analyses of complex behavior. The second aim is to use the optimized technologies to image calcineurin-dependent behaviors. The third aim is to screen for novel treatments of calcineurin-related neural dysfunction. Overall, successful completion of these aims will expand the methodologies for high-throughput analyses of complex behaviors, provide a better basic understanding of calcineurin signaling in the brain, and contribute to the design of novel treatments for calcineurin-related neural dysfunction. The project will benefit from the vibrant and collegial research environment at Brown University. The principal investigator has a primary appointment in the Department of Molecular Biology, Cell Biology and Biochemistry and is a faculty member in the Carney Institute for Brain Science and the Center to Advance Predictive Biology. The department offers expertise in developmental biology and cell signaling and the two centers provide a dynamic intellectual environment for research in behavioral neuroscience and the analysis of signaling networks using high-content imaging technologies.