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

用于自动分析钙调神经磷酸酶依赖性脑功能的新兴成像技术

• 批准号: 10119829
• 负责人: ROBBERT J CRETON
• 金额: $ 31.7万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119829
• 关键词: Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Model; Appointment; Behavior; Behavioral; Behavioral Assay; Biochemistry; Biological Assay; Biological Models; Biology; Bladder; Brain; Calcineurin; Calcineurin inhibitor; Calcium; Cellular biology; Chromosome 21; Clinical Research; Complex; Development; Developmental Biology; Down Syndrome; Drug Screening; Environment; Faculty; Fertilization; Fetal Development; Food; Genes; Goals; Image; Image Analysis; Imaging technology; Immune system; Immunosuppressive Agents; Institutes; Laboratories; Larva; Lead; Life; MAPT gene; Measurement; Measures; Mental disorders; Methodology; Molecular Biology; Morphology; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Neurosciences; Organ; Outcome; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Protein Serine/Threonine Phosphatase; Proteins; Research; Risk; Role; Science; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Structure; Swimming; Technology; Testing; Time; Tyrosine Phosphorylation; Universities; Zebrafish; automated analysis; automated image analysis; avoidance behavior; base; body system; clinically significant; design; developmental disease; environmental toxicology; high throughput analysis; imaging capabilities; imaging system; improved; inhibitor/antagonist; member; neural network; novel; novel imaging technology; nuclear factors of activated T-cells; organ transplant rejection; overexpression; prevent; prototype; relating to nervous system; repaired; response; small molecule; small molecule libraries; standard measure; tool; transplantation medicine; visual stimulus

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.

项目概要 钙调磷酸酶是一种具有广泛临床意义的磷酸酶，用作钙调磷酸酶抑制剂。 免疫抑制剂可防止器官移植排斥，而钙调神经磷酸酶信号传导被认为发挥了重要作用 然而，人们对唐氏综合症和阿尔茨海默病的影响知之甚少。 大脑中调节钙调神经磷酸酶信号传导的动物模型系统是可用的，但神经元会发生变化。 在研究像大脑这样复杂的器官时，网络很容易被忽视。 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。 首席研究员开发了一种成像系统，用于自动分析斑马鱼幼虫的行为。 该成像系统可以测量幼虫对微孔板中移动视觉刺激的反应，这不是 该成像系统的功能将进一步增强。 扩展用于 384 孔格式的复杂行为的自动分析 该项目由 中心假设是用于脊椎动物行为高通量分析的新型成像技术将 有助于发现神经功能障碍的新疗法。这一假设将在三个方面得到检验。 具体目标是优化复杂的高通量分析的成像技术。 第二个目标是使用优化技术对钙依赖磷酸酶依赖性行为进行成像。 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疗法，总体而言是成功的。 完成这些目标将扩展复杂行为高通量分析的方法， 提供对大脑中钙调磷酸酶信号传导更好的基本了解，并有助于设计新颖的 该项目将受益于充满活力和学院氛围的神经功能障碍的治疗。 布朗大学的研究环境主要由首席研究员担任。 分子生物学、细胞生物学和生物化学系，卡尼医学院教员 脑科学研究所和高级预测生物学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导，这两个中心为 使用高内涵成像进行行为神经科学研究和信号网络分析 技术。