NSF/BIO-DFG: Tuning Microtubule-Actin crosstalk to control Mitotic Fidelity

NSF/BIO-DFG：调节微管-肌动蛋白串扰以控制有丝分裂保真度

• 批准号: 2319918
• 负责人: Linda Wordeman
• 金额: $ 48.83万
• 依托单位: University of Washington
• 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: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2319918&HistoricalAwards=false
• 关键词: NSF; BIO; DFG; Tuning; Microtubule

Microtubules are relatively long cellular polymers that continuously grow and shrink in a dynamic yet controlled manner. They are also responsible for segregating chromosomes with perfect fidelity during cell division. Previously it has been found that measurable disturbances in dynamic microtubule growth that do not superficially appear abnormal will promote intermittent errors in chromosome segregation through an unknown mechanism. As everyone who owns a car knows, intermittent defects are the most challenging to diagnose. However, strong preliminary evidence indicates that these small changes in microtubule assembly may temporarily promote the delivery of molecules to the cell outer cortex that interfere with the mitotic spindle’s ability to position itself in space. This, in turn, increases the rate that cells make errors during cell division. Describing this biological phenomenon will prove important to understand the regulation of growth and development in both plants and animals. The Broader Impacts of the work includes its intrinsic merit as all dividing eukaryotic cells employ microtubes for division. Moreover, errors in the process can result in a variety of human maladies. Additional activities include the training of undergraduate and graduate students in research methods and incorporation of the research into an existing course.This project will employ high resolution live imaging, atomic force microscopy and actin reporters to catch mitotic spindles “in the act” of temporarily losing spatial positioning during controlled experimental alteration of microtubule growth rates. A custom method of quantifying attachment errors using super-resolution expansion microscopy will be employed to directly correlate the number of segregation errors commensurate with spindle orientation. The project includes developmental systems to determine the extent to which these mechanisms, initially described in cell culture, are utilized during normal development and in the establishment of tissue architecture.This collaborative US/German project is supported by the US National Science Foundation (NSF) and the Deutsche Forschungsgemeinschaft (DFG) where NSF funds the US investigator and DFG funds the German partner.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.

微管是相对长的细胞聚合物，其以动态但受控的方式连续生长和收缩。它们还负责在细胞分裂期间以完美的保真度分离染色体。以前已经发现，表面上看不出异常的动态微管生长中的可测量的干扰将通过未知的机制促进染色体分离中的间歇性错误。正如每个拥有汽车的人都知道的那样，间歇性故障是最难诊断的。然而，强有力的初步证据表明，微管组装中的这些微小变化可能会暂时促进分子向细胞外皮层的传递，从而干扰有丝分裂纺锤体在空间中定位的能力。这反过来又增加了细胞分裂过程中出错的几率。描述这一生物学现象对于理解植物和动物的生长和发育的调节是很重要的。这项工作的更广泛影响包括其内在的优点，因为所有分裂的真核细胞都使用微管进行分裂。此外，这一过程中的错误可能导致各种人类疾病。其他活动包括本科生和研究生的研究方法的培训和研究纳入现有course.This项目将采用高分辨率实时成像，原子力显微镜和肌动蛋白报告捕捉有丝分裂纺锤体的“行为”暂时失去空间定位在可控的实验改变微管生长率。将采用使用超分辨率扩展显微镜量化附着误差的自定义方法来直接关联与主轴方向相称的分离误差的数量。该项目包括开发系统，以确定这些机制在多大程度上，最初描述在细胞培养，在正常发育和组织结构的建立过程中使用。这个美国/德国合作项目由美国国家科学基金会（NSF）和德国研究共同体（DFG）支持。其中NSF资助美国研究者，DFG资助德国合作伙伴。该奖项反映了NSF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进行评估，被认为值得支持的搜索.