Collaborative Research: Master-Slave Clock Networks: Modeling, Analysis and Neurobiology

计算和神经生物学方法的结合将用于探索哺乳动物产生内源性每日（昼夜节律）节律的机制。主昼夜节律起搏器位于下丘脑视交叉上核（SCN）内，由数千个细胞自主振荡器组成。这项工作的一个目标是建立一种脑切片制备，其中荧光素酶报告器允许我们实时跟踪关键时钟基因表达的振荡。研究人员将专注于识别基因的转录-翻译反馈回路，这些基因的表达对昼夜节律至关重要。分子方法将被用来选择性地中和特定基因的表达，并检查这种操作对起搏器和从属振荡器的影响。特别地，主振子和它在室旁区阻尼从振子之间的关系将被研究；后者包括SCN的主要输出，中央时钟通过SCN调节生物体其余部分的大部分生理和行为。这项工作的智力价值集中在计算建模与神经生物学和分子方法的协调上。它将扩展到分布振子之间的相互作用。这项工作的更广泛影响包括其应用于理解由时差和轮班工作引起的健康状况。此外，这项研究将在马萨诸塞大学阿姆赫斯特分校和美国最大的女子文理学院史密斯学院进行。本科生和研究生将有机会与活跃的研究人员导师一起使用最先进的设备进行动手实验。这一合作努力将为妇女和代表性不足的少数民族提供获得数学、科学和工程前沿培训的机会。教学工作将与史密斯学院新成立的Picker工程项目相结合。定期召开会议，学生和教师在会上回顾当前的文献关于生物钟。这项研究的合作和跨学科性质吸引了来自不同背景的学生和教师，包括神经科学、生物学、计算机科学和工程学。

A combination of computational and neurobiological methods will be used to explore the mechanisms which generate endogenous daily (circadian) rhythms in a mammal. The master circadian pacemaker, which resides within the suprachiasmatic nucleus of the hypothalamus (SCN), is comprised of thousands of cell-autonomous oscillators. One objective of this work is to establish a brain slice preparation in which a luciferase reporter allows us to track oscillations in the expression of critical clock genes in real time. The researchers will focus on identified transcriptional-translational feedback loops of genes whose expression is critical to circadian rhythmicity. Molecular methods will be used to selectively neutralize the expression of specific genes, and to examine the effects of such manipulations on the pacemaker and subordinate oscillators. In particular, the relationship between the master oscillator and its damping slaves in the subparaventricular zone will be investigated; the later comprises the major output of the SCN through which the central clock regulates much of the physiology and behavior of the rest of the organism.The intellectual merit of this work is centered upon coordination of the computational modeling with neurobiological and molecular approaches. It will extend to interactions among distributed oscillators. The broader impact of this work includes its application to understanding the health-related conditions arising from jet lag and shift work. Furthermore, this research will be carried out both at the University of Massachusetts at Amherst and at Smith College, the nation's largest liberal arts college for women. Undergraduate and graduate students will have opportunities to conduct hands-on experiments using state-of-the art equipment, working with mentors who are active researchers. This collaborative efforts will offer opportunities for women and under-represented minorities to gain training at the cutting edge of mathematics, science and engineering. The instructional efforts will be integrated with the newly formed Picker Engineering Program at Smith College. Regular meetings will be held, at which students and faculty review the current literature on biological clocks. The collaborative and interdisciplinary nature of this research draws together students and faculty from diverse backgrounds including Neuroscience, Biology, Computer Science, and Engineering.