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Regulation of Calcium Signaling by the Intrinsic Cell Death Pathway in C. elegans

线虫内在细胞死亡途径对钙信号传导的调节

基本信息

批准号：
1753742
负责人：
Keith Nehrke
金额：
$ 49.32万
依托单位：
University of Rochester
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1753742&HistoricalAwards=false
关键词：
Regulation Calcium Signaling Intrinsic Cell

项目摘要

Calcium, and regulating its concentration, are essential for life. Changes in calcium concentration are used to convey diverse types of information within cells (intracellular calcium signaling). The particular physiological outputs of calcium signaling cascades are exquisitely dependent upon spatial and temporal constraints. A variety of proteins help to shape calcium signals, and in mammals this regulation can be extremely complex. The nematode worm Caenorhabditis elegans is a model organism that is widely used for genetic approaches and exhibits many of the same constraints on calcium signaling as mammals. The use of this model allows researchers to circumvent the complexities of mammalian systems and more directly show cause and effect through advanced genomic editing approaches and integrative physiology. Specifically, this project will investigate how the interaction between two classes of proteins that are central to calcium signaling regulates physiological and behavioral outputs. The Nehrke Lab is strongly committed to promoting community interactions and diversity in science and to training the next generation of scientists. Toward these ends, the project will continue to provide STEM education to Rochester City School District third-graders through an outreach program at the YMCA and will initiate a joint training program with Monroe Community College that allows students to rotate among a variety of University of Rochester Medical Center laboratories during the academic year and then to undertake a ten-week summer research fellowship in one of those labs.The inositol 1, 4, 5-trisphosphate receptor (IP3R) is an endoplasmic reticular (ER) Ca2+ release channel whose activity is central to Ca2+ signaling. Fine-tuning of IP3R activity by other proteins diversifies its signaling repertoire. Recent evidence indicates that anti-apoptotic Bcl-2 family members interact with the IP3R and that this may facilitate ER-to-mitochondrial Ca2+ transfer to promote oscillatory Ca2+ signaling rather than apoptotic Ca2+ overload. In mammals, studying the role of IP3R/Bcl-2 interactions is complicated by multiple IP3R isoforms and Bcl-2 family members that share contact sites with the receptor, making it difficult to address specific cause and effect. In contrast, C. elegans has only a single isoform of each protein, which nevertheless perform similar functions and possess nearly identical amino acid sequences to their mammalian counterparts at the sites of interaction. Sophisticated genetic tools, including CRISPR-Cas9 mediated genome editing to create "loss-of-interaction" models and cutting-edge approaches using biosensors to measure localized calcium signaling, will be used to test this hypothesis and to interrogate the underlying mechanisms. Research results will increase understanding of inter-organelle communication and its relevance to normal physiology. The award supports a successful and long-standing outreach program aimed at Rochester City School District third-grade students, who are among the most impoverished in the country. In addition, a new initiative will synergize with existing local infrastructure to create shadowing and summer research traineeships for underrepresented Monroe Community College students continuing on to four-year universities. Research training for a postdoctoral fellow and mentoring experience for two graduate students will also be provided.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

钙和调节其浓度对生命至关重要。钙浓度的变化用于在细胞内传递不同类型的信息（细胞内钙信号）。钙信号级联的特定生理输出精确地依赖于空间和时间的限制。多种蛋白质有助于形成钙信号，在哺乳动物中，这种调节可能非常复杂。线虫秀丽隐杆线虫是广泛用于遗传方法的模式生物，并且表现出许多与哺乳动物相同的对钙信号传导的限制。该模型的使用使研究人员能够绕过哺乳动物系统的复杂性，并通过先进的基因组编辑方法和综合生理学更直接地显示因果关系。具体来说，该项目将研究两类蛋白质之间的相互作用是如何调节生理和行为输出的钙信号的核心。Nehrke实验室致力于促进社区互动和科学多样性，并培养下一代科学家。为了实现这些目标，该项目将继续通过基督教青年会的外展计划为罗切斯特市学区的三年级学生提供STEM教育，并将与门罗社区学院启动一项联合培训计划，允许学生在学年期间在罗切斯特大学医学中心的各种实验室之间轮换，然后在其中一个实验室进行为期十周的夏季研究奖学金。4，5-三磷酸受体（IP 3R）是内质网Ca ~（2+）释放通道，其活性与Ca ~（2+）信号转导密切相关。其他蛋白质对IP 3R活性的微调使其信号库多样化。最近的证据表明，抗凋亡Bcl-2家族成员与IP 3R相互作用，这可能有助于ER向线粒体Ca 2+转移，以促进振荡Ca 2+信号传导，而不是凋亡Ca 2+过载。在哺乳动物中，研究IP 3R/Bcl-2相互作用的作用是复杂的，因为多种IP 3R亚型和Bcl-2家族成员与受体共享接触位点，使得难以解决特定的因果关系。与之相比，C.秀丽隐杆线虫的每种蛋白质只有一种同种型，但它们与哺乳动物的对应蛋白质在相互作用位点具有相似的功能和几乎相同的氨基酸序列。复杂的遗传工具，包括CRISPR-Cas9介导的基因组编辑以创建“失去相互作用”模型，以及使用生物传感器测量局部钙信号传导的尖端方法，将用于测试这一假设并询问潜在的机制。研究结果将增加对细胞器间通信及其与正常生理学相关性的理解。该奖项支持一个成功的和长期的推广计划，旨在罗切斯特市学区三年级学生，谁是在该国最贫困的。此外，一项新的举措将与现有的地方基础设施协同作用，为继续进入四年制大学的代表性不足的门罗社区学院学生创造影子和夏季研究培训机会。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。