Analysis of the Regulation of G protein-Coupled Sensory Signaling in C. Elegans

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。所有的动物都依靠它们对不断变化的环境的感知和反应能力来生存。由于没有眼睛和耳朵，秀丽隐杆线虫（小蛔虫）在很大程度上依赖于它们品尝和嗅觉土壤环境中化学信息的能力来寻找食物和避免危险；动物必须向表明食物来源的化学物质移动，同时避开表明潜在有害环境的化学物质。当化学信号（味觉剂和嗅觉剂）与感觉神经细胞（神经元）上的蛋白质（受体）结合，并启动一系列细胞内事件，最终激活神经元时，就会引发这些行为反应。反过来，神经元的活动控制着生物体的行为。尽管这一化学信号转导过程在物种间高度保守，但我们对调节信号传导的机制的理解仍然存在很大差距。再加上强大的遗传和分子工具，秀丽隐杆线虫是一个理想的模型系统，在其中解剖单个基因和调控途径对综合神经元功能和感觉行为的贡献。信号负调节因子（秀丽隐杆线虫GRK-2）的缺失令人惊讶地导致感觉神经元中钙信号的减少，并同时导致吸引和回避化学感觉行为的缺失。在缺乏GRK-2的情况下，代偿抑制通路似乎上调，抑制信号传导以保护神经元免受过度刺激。该项目将在一个简单的模式生物中利用细胞、生化和遗传方法来了解细胞如何对异常信号作出反应；这些发现将使研究从酵母到人类等生物的研究人员受益。特别是，它们将为受体下游信号传导和调控途径的相互联系提供有价值的信息。此外，细胞用于补偿失调信号的新机制可能会被揭示。更广泛的影响研究生和本科生，包括女性和少数民族学生，将参与这些研究。布法罗大学（UB）是一个非常多元化的校园，为指导少数民族学生提供了很好的机会。这笔资金将用于支持文理学院本科生的夏季津贴，文理学院本身没有本科生研究。让学生尽早接触到假设驱动的研究，对于让他们为从事生物科学的职业做好准备至关重要。学生将在当地（每月）、区域和国际会议上展示他们的研究成果。重要的是，一年一度的秀丽隐杆线虫会议促进了年轻科学家的发展，因为许多演讲者是从研究生提交的摘要中挑选出来的。这项工作的发现也将包括在UB的本科生信号转导课程的讲座中。在这个项目中从基因筛选中获得的突变体将被存放在隐杆线虫遗传中心，该中心将把它们分发给任何需要它们的研究者。新的基因和表型描述也将纳入在线开放获取资源Wormbase。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).Intellectual MeritAll animals rely on their ability to sense and respond to their constantly changing environments to survive. Because they do not have eyes or ears, C. elegans (small roundworms) depend heavily upon their ability to taste and smell chemical information in their soil environment to find food and avoid danger; animals must move towards chemicals that indicate a food source while avoiding chemicals that indicate potentially harmful environments. These behavioral responses are elicited when the chemical signals (tastants and odorants) bind to proteins (receptors) on sensory nerve cells (neurons) and initiate a chain of intracellular events that ultimately activates the neuron. Neuronal activity, in turn, controls the behavior of the organism. Although this process of chemical signal transduction is highly conserved across species, there are still large gaps in our understanding of the mechanisms used to regulate signaling. Coupled with powerful genetic and molecular tools, C. elegans is an ideal model system in which to dissect the contributions of individual genes and regulatory pathways to integrated neuronal function and sensory behavior. Loss of a negative regulator of signaling (C. elegans GRK-2) surprisingly leads to decreased calcium signaling in sensory neurons and a concomitant loss of both attractive and avoidance chemosensory behaviors. In the absence of GRK-2 there appears to be an upregulation of compensatory inhibitory pathways that dampen signaling to protect neurons from overstimulation. This project will utilize cellular, biochemical and genetic approaches in a simple model organism to understand how cells respond to aberrant signaling; the findings will benefit researchers working in organisms ranging from yeast to humans. In particular, they will provide valuable information on the interconnectedness of signaling and regulatory pathways downstream of receptors. In addition, novel mechanisms used by cells to compensate for mis-regulated signaling may be revealed. Broader ImpactGraduate students and undergraduates, including women and minority students, will participate in these studies. The University at Buffalo (UB) is a very diverse campus, providing a great opportunity to mentor minority students. Funds from this grant will support a summer stipend for an undergraduate from a Liberal Arts College that does not itself have undergraduate research. Providing early exposure to hypothesis-driven research is essential for preparing students for careers in the biological sciences. Students will present their findings at local (monthly), regional and international meetings. Importantly, the annual C. elegans meetings foster the development of junior scientists because many of the speakers are selected from graduate student submitted abstracts. Findings from this work will also be included in the lectures in an undergraduate Signal Transduction course at UB. Mutants obtained from the genetic screens in this project will be deposited at the Caenorhabditis Genetics Center, which will distribute them to any investigator that requests them. New gene and phenotype descriptions will also be incorporated into Wormbase, an online open access resource.