Collaborative Research: RUI: Comparative analysis of endocytic trafficking during cell division

合作研究：RUI：细胞分裂过程中内吞运输的比较分析

• 批准号: 2052517
• 负责人: Bradley Davidson
• 金额: $ 86.2万
• 依托单位: Swarthmore College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2052517&HistoricalAwards=false
• 关键词: Collaborative; Research; RUI; Comparative; analysis

This research project explores the interplay between cell division and the signals that cells exchange to coordinate their behavior. This is a critical area of investigation because signal-dependent coordination of cell behavior is essential for the growth of all life forms. Signaling also plays a crucial role in dividing stem cells, ensuring that the proper number of stem cells are available to participate in tissue renewal and repair. Additionally, errors in signaling are the primary cause of cancer. Because cancer also entails unregulated cell division, it is particularly important to understand how division may exacerbate signaling errors. To explore this fundamentally important question, this collaborative research project encompasses three institutions, Princeton University, Swarthmore College and Colby College. The combined expertise will enable comprehensive investigations of signaling in dividing cells using an array of organisms, along with cutting edge genetic manipulation and imaging technologies. Additionally, this collaboration will pursue an ambitious outreach program which will include – 1) providing enriching research experiences for a diverse group of undergraduates, 2) development of a class focused on cancer biology for elementary school students in an underserved school district as part of the established Science for Kids summer program at Swarthmore College, 3) integration between Summer Scholars Programs at Colby, Princeton and Swarthmore which focus on preparing URM and other diverse students for a successful college transition and 4) teacher-training opportunities at the Colby Center for Teaching and Learning for Princeton post-docs who will be teaching courses in the Colby January Term program. Cellular trafficking of receptors and associated membrane proteins can profoundly impact cell signaling. Due to the long-held assumption that membrane trafficking is shut down during mitosis, current research has not addressed fundamental questions regarding the nature and regulation of trafficking in dividing cells. In particular, the contributions of mitotic kinases to endocytic trafficking remain poorly characterized. Additionally, the roles of specific endocytic pathways have not been delineated. This project aims to fill these critical gaps through a collaborative effort incorporating two experimental systems in which prior research has demonstrated an essential role for mitotic trafficking: polarization of mammalian epidermal cells and induction of heart progenitor cells in the basal chordate, Ciona intestinalis. It will investigate two hypotheses; 1) Cyclin dependent kinase 1 (CDK1) suppresses lysosomal degradation in a cargo-specific manner. 2) CDK1 and Aurora Kinase (AurK) suppress recycling broadly during mitosis. These hypotheses will be examined with well-established methods that disrupt specific mitotic kinases and endocytic pathways and employ high-resolution live-imaging assays to visualize the impact on receptor trafficking in both model systems. By conducting these studies on a range of cargo proteins in two highly divergent cell types, these findings will provide insights into the impact of mitotic trafficking on – 1) fate decisions in developing embryos 2) re-establishment of polarity in dividing epithelial sheets and 3) signal dependent behaviors of stem cells or differentiated lineages.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.

这个研究项目探索了细胞分裂和细胞交换以协调其行为的信号之间的相互作用。这是一个关键的研究领域，因为细胞行为的信号依赖协调对于所有生命形式的生长至关重要。信号传导在干细胞分裂中也起着至关重要的作用，确保适当数量的干细胞可用于参与组织更新和修复。此外，信号错误是癌症的主要原因。由于癌症也需要不受调节的细胞分裂，因此了解分裂如何加剧信号错误尤为重要。为了探索这个根本性的重要问题，这个合作研究项目包括三个机构，普林斯顿大学，斯沃斯莫尔学院和科尔比学院。结合的专业知识将使全面的调查信号在分裂细胞使用一系列的生物体，沿着与尖端的遗传操作和成像技术。此外，这项合作将追求一个雄心勃勃的外展计划，其中将包括- 1）为不同的本科生群体提供丰富的研究经验，2）在服务不足的学区为小学生开发一门专注于癌症生物学的课程，作为斯沃斯莫尔学院既定的儿童科学暑期项目的一部分，3）整合科尔比的暑期学者项目，普林斯顿大学和斯沃斯莫尔大学，专注于为URM和其他不同的学生成功的大学过渡做准备，以及4）在科尔比教学中心为普林斯顿博士后提供教师培训机会，这些博士后将在科尔比一月学期课程中教授课程。受体和相关膜蛋白的细胞运输可以深刻地影响细胞信号传导。由于长期以来的假设，即膜运输在有丝分裂过程中关闭，目前的研究还没有解决有关分裂细胞中运输的性质和调节的基本问题。特别是，有丝分裂激酶对内吞运输的贡献仍然很差。此外，特定的内吞途径的作用尚未阐明。该项目旨在填补这些关键的差距，通过合作努力，结合两个实验系统，其中先前的研究已经证明了有丝分裂贩运的重要作用：哺乳动物表皮细胞的极化和心脏祖细胞的诱导在基底脊索动物，玻璃海鞘。它将研究两个假设：1）细胞周期蛋白依赖性激酶1（CDK 1）以货物特异性方式抑制溶酶体降解。2)CDK 1和Aurora激酶（AurK）在有丝分裂期间广泛抑制再循环。这些假设将检查与完善的方法，破坏特定的有丝分裂激酶和内吞途径，并采用高分辨率实时成像分析，以可视化的影响受体贩运两个模型系统。通过对两种高度不同的细胞类型中的一系列货物蛋白进行这些研究，这些发现将为有丝分裂运输对以下方面的影响提供见解：1）发育胚胎中的命运决定; 2）分裂上皮层中极性的重新建立;以及3）干细胞或分化谱系的信号依赖行为。该奖项反映了NSF的法定使命，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。