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: 10261526
• 负责人: ROBBERT J CRETON
• 金额: $ 31.8万
• 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/10261526
• 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。钙调磷酸酶抑制剂被用作 免疫抑制剂，以防止器官移植排斥反应和钙调神经磷酸酶信号被认为是发挥作用， 在唐氏综合症和阿尔茨海默病中起着关键作用。然而，人们对以下因素的影响知之甚少： 调节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。行为分析提供了一个 潜在的解决方案，因为大脑结构和功能的细微变化可以被检测到。的实验室 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。 这种成像系统可以测量幼虫对微板中移动视觉刺激的反应， 这对于商业上可获得的成像系统是可能的。这一成像系统的能力将进一步 扩展为384孔格式的复杂行为的自动化分析。该项目由 中心假设，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 明确的目标。第一个目标是优化成像技术，以高通量分析复杂的 行为第二个目标是使用优化的技术来成像依赖于钙调神经磷酸酶的行为。 第三个目的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 这些目标的完成将扩展用于复杂行为的高通量分析的方法， 提供了对大脑中钙调神经磷酸酶信号传导的更好的基本理解，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。该项目将受益于充满活力和合议 布朗大学的研究环境。主要研究者在 分子生物学，细胞生物学和生物化学系，是卡尼大学的一名教员。 脑科学研究所和预测生物学研究中心。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和两个中心提供了一个动态的智力环境， 行为神经科学研究和使用高内容成像的信号网络分析 技术.