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Regulation of selective endocytic transport

选择性内吞转运的调节

基本信息

批准号：
2313900
负责人：
Santiago Di Pietro
金额：
$ 94.99万
依托单位：
Colorado State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2313900&HistoricalAwards=false
关键词：
Regulation selective endocytic transport

项目摘要

This project will investigate the cellular machinery that carries out endocytosis, a process in which a portion of the cell membrane is pulled into the cell interior. Endocytosis regulates how cells take up nutrients, communicate with other cells, and adapt to changes in environmental conditions. While this research will be performed using yeast, discoveries will be broadly applicable because the cellular components that mediate endocytosis are conserved among different species. Studying endocytosis is essential to understanding how cells function, and this knowledge could have a number of applications such as improving crop yields and food production. This project will contribute to supporting diversity in science and education through training of high school, undergraduate and graduate students, many of whom belong to groups underrepresented in the sciences. Both undergraduate and graduate students who work on this project will be involved in outreach at elementary schools where young students will perform hands-on yeast experiments and visualize cellular components using state-of-the-art research microscopes. The main goal of this outreach activity is to excite young students about science. Knowledge gained through this research will be published in wide-ranging scientific journals, presented at both specialized and broad cell biology conferences, and integrated into undergraduate and graduate courses taught by the researchers. During clathrin-mediated endocytosis, branched actin polymerization provides force needed to drive vesicle internalization. This research will explore three essential and unresolved questions regarding the regulation of the actin network during endocytosis. Aim 1 will establish how actin polymerization is initiated at sites of endocytosis. In particular, Aim 1 will elucidate the molecular mechanism that controls initiation of each new branch of the actin network. Aim 2 will determine the mechanism by which actin capping protein is recruited to sites of endocytosis and how two poorly understood protein components of the endocytic machinery actin network (Aim21 and Bsp1) regulate its function. Aim 3 will define the function of Twinfilin at endocytic sites. While Twinfilin has long been known as a component of actin networks, its cellular function is controversial, with recent high-profile articles reaching disparate conclusions. This project will test the premise that Twinfilin functions downstream of capping protein as an actin filament uncapping and disassembly factor at sites of endocytosis. The powerful Saccharomyces cerevisiae system will allow for the study of endocytosis regulators both in vivo and in vitro. The research will be multidisciplinary employing yeast genetics, live cell fluorescence microscopy, electron microscopy and cryo-electron tomography, biochemistry, X-ray protein crystallography, equilibrium binding assays and kinetic assays, as well as modeling approaches.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.

这个项目将研究进行内吞作用的细胞机制，内吞作用是一个细胞膜的一部分被拉入细胞内部的过程。内吞作用调节细胞如何吸收营养，与其他细胞沟通，并适应环境条件的变化。虽然这项研究将使用酵母进行，但发现将广泛适用，因为介导内吞作用的细胞组分在不同物种中是保守的。研究内吞作用对于了解细胞如何发挥功能至关重要，这一知识可以有许多应用，例如提高作物产量和粮食产量。该项目将通过培训高中生、本科生和研究生，促进支持科学和教育的多样性，其中许多人属于科学领域代表性不足的群体。从事该项目的本科生和研究生都将参与小学的外展活动，在那里，年轻学生将进行动手酵母实验，并使用最先进的研究显微镜观察细胞成分。这项推广活动的主要目标是激发年轻学生对科学的兴趣。通过这项研究获得的知识将发表在广泛的科学期刊上，在专业和广泛的细胞生物学会议上发表，并融入研究人员教授的本科和研究生课程。在网格蛋白介导的内吞作用中，分支肌动蛋白聚合提供了驱动囊泡内化所需的力。本研究将探讨三个基本的和未解决的问题，关于肌动蛋白网络的调节过程中的内吞作用。目的1将建立肌动蛋白聚合是如何启动网站的内吞作用。特别地，目标1将阐明控制肌动蛋白网络的每个新分支的起始的分子机制。目的2将确定肌动蛋白帽蛋白被招募到内吞作用位点的机制，以及内吞机制肌动蛋白网络（Aim21和Bsp 1）的两个知之甚少的蛋白组分如何调节其功能。目的3将确定Twinfilin在内吞位点的功能。虽然Twinfilin长期以来一直被认为是肌动蛋白网络的一个组成部分，但其细胞功能是有争议的，最近备受瞩目的文章得出了不同的结论。本项目将测试Twinfilin作为内吞作用位点的肌动蛋白丝脱帽和分解因子在帽蛋白下游发挥作用的前提。强大的酿酒酵母系统将允许在体内和体外研究内吞作用调节剂。该研究将是多学科的，采用酵母遗传学，活细胞荧光显微镜，电子显微镜和冷冻电子断层扫描，生物化学，X射线蛋白质晶体学，平衡结合分析和动力学分析，以及建模approaches.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。