Mitochondrial Regulation of Calcium Signaling in C. elegans

秀丽隐杆线虫表达一种节律性行为，其时间由振荡Ca2+信号控制。这种行为在解剖学上很简单，肠道、几个肌肉细胞和两个神经元相互交流，建立排便运动程序（DMP）。肠后部细胞是行为起搏器，规范的信号级联调节基础，节律Ca2+振荡在这些细胞中已经很好地表征。然而，这些振荡也有助于建立代谢稳态，并与促进营养吸收的离子运输过程相结合。该奖项支持的研究将使我们能够确定这些过程整合的潜在机制，特别是关注细胞的代谢中心——线粒体。线粒体的主要功能是通过氧化磷酸化传递能量，这一过程产生了细胞中大部分内源性ROS。然而，线粒体也被公认为通过缓冲Ca2+来促进Ca2+信号传导。最近的突破性工作揭示了新的分子机制，有助于线粒体Ca2+摄取，维持细胞器特异性蛋白质稳态，并通过ROS信号传导。本研究的每个目的都是为了查询线粒体功能的这些特定方面，以及它们对振荡Ca2+信号的影响。我们将研究线粒体Ca2+摄取、线粒体未折叠蛋白反应（UPRmt）和线粒体活性氧（ROS）产生在维持行为节律性和代谢稳态中的作用。该项目将包括为代表性不足的少数民族学生提供培训和研究机会。此外，一个新的K-12学习计划将由实验室的前博士后实习生开发和领导，他来自一个代表性不足的背景，在这一领域拥有丰富的经验。此外，我们亦会建立及扩展一个网站，以促进与利益相关者的沟通，并传播透过我们的学习计划所开发的教学模块。结果将通过出版物传播，但基础数据集将应要求免费提供。在项目过程中开发的有用的秀丽隐杆线虫菌株将通过秀丽隐杆线虫遗传学联盟（http://www.cbs.umn.edu/research/resources/cgc）向公众提供。新型质粒和分子生物试剂将由Addgene （https://www.addgene.org/）处理。

The nematode Caenorhabditis elegans expresses a rhythmic behavior whose timing is controlled by oscillatory Ca2+ signaling. The behavior is anatomically simple, with the intestine, several muscle cells, and two neurons communicating to establish the defecation motor program (DMP). The posterior cells of the intestine are the behavioral pacemaker, and the canonical signaling cascades that regulate basal, rhythmic Ca2+ oscillations in these cells have been well-characterized. However, these oscillations also help to set metabolic homeostasis and are coupled to ion transport processes that facilitate nutrient uptake. The research supported by this award will allow us to identify the underlying mechanisms through which these processes are integrated, focusing in particular on the metabolic hub of the cell, the mitochondria. The main function of mitochondria is to transduce energy through oxidative phosphorylation, a process which generates most of the endogenous ROS in cells. However, mitochondria are also well-recognized to contribute to Ca2+ signaling by buffering Ca2+. Recent groundbreaking work has uncovered novel molecular mechanisms that contribute to Ca2+ uptake by mitochondria, to maintaining organelle-specific protein homeostasis, and to signaling through ROS. Each of the aims in this study is intended to query these specific aspects of mitochondria's function with respect to their effect on oscillatory Ca2+ signaling. We will investigate the role of mitochondrial Ca2+ uptake, the mitochondrial unfolded protein response (UPRmt) and mitochondrial reactive oxygen species (ROS) generation in maintaining behavioral rhythmicity and metabolic homeostasis. The project will include training and research opportunities for under-represented minority students. Furthermore, a new K-12 learning program will be developed and led by a former postdoctoral trainee from the lab who comes from an under-represented background and has extensive experience in this area. A website will also be developed and expanded to facilitate communication with the stakeholder community and to disseminate teaching modules developed through our learning program. Results will be disseminated through publication, but the underlying data sets will be made freely available upon request. Useful c. elegans strains developed during the course of the project will be made publically available through the C. elegans Genetics Consortium (http://www.cbs.umn.edu/research/resources/cgc). Novel plasmids and molecular biological reagents will be handled by Addgene (https://www.addgene.org/).