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Regulation of glutamate receptor trafficking by VER/VEGF receptors in the nervous system of C. elegans

线虫神经系统中 VER/VEGF 受体对谷氨酸受体运输的调节

基本信息

批准号：
1941073
负责人：
Peter Juo
金额：
$ 99.65万
依托单位：
Tufts University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1941073&HistoricalAwards=false
关键词：
Regulation glutamate receptor trafficking VER

项目摘要

This project studies how a molecule that was originally described as a blood vessel development growth factor also controls communication between nerve cells in the roundworm Caenorhabditis elegans. While all the molecular pathways studied here are present in vertebrate animals including humans, these experiments are conducted in roundworms because they have a compact and defined nervous system, are amenable to genetic manipulation and, in particular, do not have any blood vessels. This makes it possible to avoid confounding effects that changes in vascular development might indirectly have on neural development. Results from this project will advance scientific understanding of nerve cell signaling and plasticity; this research may also identify new genes and molecular pathways important for learning and memory. A complementary outreach plan will develop an instructional research module for use at local public high schools, and a full-semester neurobiology lab course for undergraduates where students have a real opportunity to generate new scientific knowledge that could develop into an independent research project. In the process of performing the proposed research aims, this project will also train graduate students and provide hands-on independent research opportunities for undergraduates, for educators, and for under-represented minorities in a dedicated summer program.The modulation of synaptic strength via activity-dependent changes in glutamate receptor (GluR) abundance at synapses is a major mechanism underlying learning and memory. While previous work has identified the molecular mechanisms that directly traffic GluRs to and from synapses, less is known about in-vivo secreted factors that act on these receptor trafficking pathways. Preliminary studies from the Principal Investigator’s laboratory have used an optogenetic glutamatergic behavior screen in C. elegans to identify the Vascular Endothelial Growth Factor Receptor (VEGFR) homologs ver-1 and ver-4, which are activated by the secreted VEGF homolog PVF-1. Data also suggest that VER-1 and VER-4, and the ligand PVF-1, regulate both cell surface levels of the GluR GLR-1 and glutamatergic behaviors in C. elegans. The goal of this proposal is to investigate whether regulated secretion of PVF-1/VEGF activates neuronal VER/VEGFR signaling to modulate GLR-1/GluR recycling to the cell surface, thereby impacting behavior. C. elegans is a particularly suitable organism for these studies because of their lack of vasculature, allowing these experiments on the neural effects of VEGFRs to be free of confounds from the vasculature. This work will elucidate the mechanisms by which VER signaling within neurons regulates GLR-1 trafficking, and how PVF-1 expression or secretion are regulated in vivo to modulate GLR-1 abundance and behavior. This study may reveal novel details about the fundamental and conserved mechanisms through which VEGFRs contribute to nervous system function.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.

该项目研究了一种最初被描述为血管发育生长因子的分子如何控制线虫中神经细胞之间的通讯。虽然这里研究的所有分子途径都存在于包括人类在内的脊椎动物中，但这些实验是在蛔虫中进行的，因为它们具有紧凑和明确的神经系统，易于遗传操作，特别是没有任何血管。这使得有可能避免血管发育的变化可能间接影响神经发育的混淆效应。该项目的结果将促进对神经细胞信号传导和可塑性的科学理解;这项研究还可能确定对学习和记忆重要的新基因和分子通路。一个补充的推广计划将开发一个教学研究模块，供当地公立高中使用，并为本科生提供一个整学期的神经生物学实验室课程，学生有真实的机会产生新的科学知识，这些知识可以发展成为一个独立的研究项目。在执行拟议的研究目标的过程中，该项目还将培养研究生，并在专门的暑期项目中为本科生、教育工作者和代表性不足的少数民族提供动手独立研究的机会。通过突触谷氨酸受体（GluR）丰度的活动依赖性变化来调节突触强度是学习和记忆的主要机制。虽然以前的工作已经确定了直接交通GluRs的分子机制，从突触，在体内分泌的因子，这些受体运输途径的行为知之甚少。来自主要研究者实验室的初步研究已经使用了光遗传学的神经行为筛选。elegans中鉴定血管内皮生长因子受体（VEGFR）同源物ver-1和ver-4，它们被分泌的VEGF同源物PVF-1激活。数据还表明，VER-1和VER-4，以及配体PVF-1，调节细胞表面水平的GluR GLR-1和谷氨酸能行为在C。优雅的该提案的目标是研究PVF-1/VEGF的调节分泌是否激活神经元VER/VEGFR信号传导以调节GLR-1/GluR再循环至细胞表面，从而影响行为。C.秀丽线虫是特别适合于这些研究的生物体，因为它们缺乏脉管系统，使得这些关于VEGF的神经效应的实验不受脉管系统的干扰。这项工作将阐明神经元内VER信号调节GLR-1运输的机制，以及PVF-1的表达或分泌如何在体内调节GLR-1的丰度和行为。这项研究可能会揭示新的细节的基本和保守的机制，通过它的血管内皮生长因子受体有助于神经系统function.This奖项反映了美国国家科学基金会的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。