CAREER: Determining the roles of individual tubulin isotypes in cellular microtubule functions

微管是由称为微管蛋白的蛋白质组成的长细胞细丝。微管对重要的细胞过程至关重要，包括细胞分裂和神经系统的发育。复杂生物体内的细胞有多种微管蛋白，称为同型，它们相互合作组装微管。为什么细胞具有这些相似但不同的微管蛋白同种型的多种变体在很大程度上仍然未知。这个CAREER项目的目标是确定微管在不同类型的活细胞中执行不同任务的分子机制。为了进一步扩大项目的影响，首席研究员和研究小组成员将利用项目的多个方面为高中生和大学生开发基于科学的学习活动和课程。这些课程将通过旨在吸引和教育代表性不足的高中生参与与科学相关的活动和职业的项目来管理。爱荷华州立大学（Iowa State University）将为未申报专业的大学生设立一个新的学习小组，重点关注研究模式生物在科学中的优势。这个学习型团队将强调对这些生物的研究如何促进医学、农业和一般生物学知识的发展。这一努力将增加学生接触以科学为基础的职业活动的比例，加强科学素养，并培养沟通技巧。在整个项目过程中，这些活动将影响约450名学生。微管是由微管蛋白组成的细胞骨架聚合物，微管蛋白是α和β亚基的异源二聚体。绝大多数真核生物表达α和β微管蛋白的多种变体或同型。微管蛋白同型在微管功能中的作用是一个长期存在但知之甚少的问题。该项目利用多方面的方法来解决微管蛋白同型如何决定不同微管功能的基本问题。该策略利用自然发生突变的结果和重组哺乳动物微管蛋白制备的最新进展来测试特定同型如何在轴突和卵母细胞减数分裂中起作用的假设。这些上下文特异性的结果将与芽殖酵母模型中基于基因、蛋白质组学和细胞生物学的同型功能分析相补充。这项全面的研究将利用酵母系统的优势来确定微管蛋白同型定义特定微管功能的机制。总体而言，该项目的结果将产生微管蛋白同型如何介导微管过程的范例，并对理解它们如何指定不同生物中的微管活动具有重要意义。该奖项反映了美国国家科学基金会的法定使命，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。

Microtubules are long cellular filaments that are comprised of the protein building block named tubulin. Microtubules are critical for important cellular processes including cell division and development of the nervous system. The cells within complex organisms have multiple variations of tubulin, called isotypes, that cooperate to assemble microtubules. Why cells have multiple variations of these similar yet distinct tubulin isotypes remains largely unknown. The goal of this CAREER project is to determine the molecular mechanisms by which microtubules can perform diverse tasks in different types of living cells. To further broaden the impact of the project, the Principal Investigator and members of the research group will utilize multiple aspects of the project to develop science-based learning activities and curriculums for high school and college students. These curriculums will be administered through programs designed to engage and educate underrepresented high school students in science-related activities and careers. A new section of a learning team will be developed for college students at Iowa State University with undeclared majors that focuses on the advantages of studying model organisms in science. This learning team will emphasize how the study of these organisms advances medicine, agriculture and general biological knowledge. This effort will increase the proportion of students exposed to science-based career activities, strengthen science literacy, and build communication skills. These activities will impact about 450 students over the course of the project.Microtubules are cytoskeletal polymers comprised of tubulin protein, a heterodimer of alpha and beta subunits. The vast majority of eukaryotes express multiple variants, or isotypes, of alpha and beta tubulin. A long-standing yet poorly understood question is the role of tubulin isotypes in microtubule functions. This project utilizes a multifaceted approach to address the fundamental question of how tubulin isotypes dictate distinct microtubule functions. The strategy draws on results with naturally occurring mutations and recent advances in the preparation of recombinant mammalian tubulin to test hypotheses for how specific isotypes function in axons and in oocyte meiosis. These context-specific results will be complemented with genetic, proteomic and cell biological-based analyses of isotype function in the budding yeast model. This comprehensive investigation will exploit the strengths of the yeast system to define mechanisms by which tubulin isotypes define specific microtubule functions. Overall, the results of this project will generate paradigms for how tubulin isotypes mediate microtubule processes and have significant implications for understanding how they specify microtubule activities in diverse organisms.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.