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.

微管是相对较长的细胞聚合物，以动态但受控的方式持续生长和收缩，它们还负责在细胞分裂过程中完美保真地分离染色体，此前已发现动态微管生长中的可测量扰动在表面上并不显得异常。会通过一种未知的机制促进染色体分离的间歇性错误，正如每个拥有汽车的人都知道的那样，间歇性缺陷是最难诊断的，然而，强有力的初步证据表明，微管组装的这些微小变化。可能会暂时促进分子向细胞外皮层的输送，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在细胞分裂过程中出错的几率，这对于理解这种生物现象非常重要。这项工作的更广泛影响包括其内在优点，因为所有分裂的真核​​细胞都使用微管进行分裂，此外，该过程中的错误可能导致多种人类疾病，包括。的培训本科生和研究生的研究方法以及将研究纳入现有课程。该项目将采用高分辨率实时成像、原子力显微镜和肌动蛋白产生器来捕捉有丝分裂纺锤体“在受控实验改变期间暂时失去空间定位的行为”使用超分辨率扩展显微镜量化附着错误的定制方法将用于直接关联与纺锤体方向相称的分离错误数量。这些机制最初在细胞培养中描述，在正常发育和组织结构的建立过程中得到利用。这个美国/德国合作项目得到了美国国家科学基金会 (NSF) 和德国研究协会 (DFG) 的支持，其中 NSF 资助了美国调查员和 DFG 为德国合作伙伴提供资金。该奖项反映了 NSF 的法定使命，并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，被认为值得支持。