NSF Postdoctoral Fellowship in Biology FY 2022: Defining the biochemical mechanisms of microtubule shrinking and nucleation by combining innovative experiments and simulations

这一行动为NSF 2022财年生物学博士后研究奖学金提供了资金，综合研究调查了基因组、环境和表型之间相互作用的生命规则。该奖学金支持研究员的研究和培训，这些研究员将以创新的方式为生活规则领域做出贡献。大多数细胞通过细胞骨架进行生长、重塑和分裂，细胞骨架是一种蛋白质网络，起到了一种脚手架的作用，赋予细胞内部形状和结构。细胞骨架的一个关键方面是称为微管的小蛋白质亚单位。尽管经过几十年的研究，但对微管功能和行为的许多方面仍知之甚少。这位研究员将结合湿实验室实验和计算机模拟来确定新的微管是如何形成的，以及现有的微管是如何收缩的(这两种行为对微管的功能至关重要)。该奖项还支持当地科学推广计划的发展。微管收缩和自发组装(成核)率最终由αβ-微管蛋白亚基的结构和生化特性决定。要确定长度小于10 nm的亚基之间的相互作用如何决定μm尺度上的微管组装动力学仍然具有挑战性。这种不确定性限制了对微管行为如何在同一生物体中的细胞之间、不同物种之间、甚至跨分类群之间发生变化的机械理解。为了研究微管是如何收缩的，这位研究员将使用突变体-野生型混合微管的开创性测量，并辅之以动力学蒙特卡罗模拟。这种混合的计算-实验方法将以以前不可能的方式测试关于微管动力学机制的假说。为了了解新的微管是如何自发形成或成核的，该研究员将创建新的代码来模拟未聚合的αβ-微管蛋白的微管成核。通过这些模拟，这位研究员将定义导致新微管的微管蛋白寡聚体的序列，以及该序列如何依赖于αβ-微管蛋白的生化特性。培训目标包括学习先进显微镜、计算模拟和蛋白质工作方面的新技能。为了扩大对科学的参与，这位研究员将领导一个基于显微镜的外展项目，与当地一所为不同学生群体提供服务的中学合作。授课计划和材料将公开提供。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2022, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the fellow that will contribute to the area of Rules of Life in innovative ways. Most cells grow, remodel and divide using the cytoskeleton – a network of protein that function as a kind of scaffolding that gives shape and structure to the cell interior. A critical aspect of the cytoskeleton are small protein subunits called microtubules. Despite decades of study, many aspects of microtubule function and behavior are poorly understood. The Fellow will combine wet lab experiments with computational simulations to determine how new microtubules form, and how existing microtubules shrink (two behaviors critical for microtubule function). This award also supports the development of a local scientific outreach program.Microtubule shrinking and spontaneous assembly (‘nucleation’) rates ultimately derive from the structural and biochemical properties of αβ-tubulin subunits. It remains challenging to determine how interactions between subunits less than 10 nm long determine microtubule assembly dynamics on the μm scale. This uncertainty limits mechanistic understanding of how microtubule behavior can change between cells in the same organism, between different species, and even across taxa. To investigate how microtubules shrink, the Fellow will use pioneering measurements of mixed mutant-wild type microtubules complemented by kinetic Monte Carlo simulations. This hybrid computational-experimental approach will test hypotheses about mechanisms of microtubule dynamics in ways that were not previously possible. To understand how new microtubules form spontaneously, or ‘nucleate’, the Fellow will create new codes to simulate microtubule nucleation from unpolymerized αβ-tubulin. With these simulations, the Fellow will define the sequence of tubulin oligomers that leads to a new microtubule, and how the sequence depends on biochemical properties of αβ-tubulin. Training objectives include learning new skills in advanced microscopy, computational simulations and protein work. To broaden participation in science, the fellow will lead a microscope-based outreach program with a local middle school that serves a diverse student population. Lesson plans and materials will be made publicly available.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.