Active Cortical Domains Coupled by Bulk Diffusion Framework for Modeling Spatiotemporal Phenomena in Cell Biology

细胞的生长和分裂需要细胞通过形成具有不同分子成分的不同隔间来极化。错误的细胞极化会导致出生缺陷或癌症等疾病。PI将开发随机和确定性模型，以更好地了解细胞中的生化因素如何相互作用和调节，以实现适当的细胞功能。这个项目将模拟发生在细胞膜和细胞内部的化学反应的分离。这种分离被认为引起了有趣的动力学现象，例如中心极性调节器Cdc42的振荡和多个极化区的建立。区隔和几何对极化动力学的影响才刚刚开始探索，并可能导致对细胞如何维持细胞极性的新的生物学见解。PI的长期教育目标是鼓励女性本科生和研究生在STEM领域追求职业生涯，特别是在应用数学领域。更广泛的教育影响将包括在圣母大学为本科生和研究生组织一次讲习班。PI将专注于在分裂酵母和萌芽酵母中建立极性，这两种模式生物用于理解细胞如何整合极性和生长的空间协调。目前使用反应扩散方程模拟细胞极性的数学方法没有考虑细胞内极性分子的空间分离。这个项目的目标是通过将整体扩散耦合到活性表面结合的化学物种来模拟细胞极化过程中发生的细胞信号。PI将把这种体表PDE框架应用于特定的科学目标：(1)将确定性的体细胞溶质1D模型框架扩展到描述潜在生化系统中固有噪声的空间随机模型框架，并使用基于隔室的SSA方法比较增加细胞大小和分子数量的模型结果；(2)将1D框架扩展到更高的维度，其中皮质区域被模拟为允许横向扩散的薄片，胞质溶质被建模为封闭的体积，并考虑细胞几何对细胞内信号的影响。这一建议的教育目标是：1)为本科生组织一个研讨会，鼓励她们在应用数学和其他STEM领域从事职业；2)参加圣母大学STEM项目的女性领导者项目；3)为数学细胞生物学研究生课程开发新材料，向跨学科学生开放；4)在现有的国家教育项目中授课，如Q-BIO暑期学校，向不同学科的学生，如数学、物理和计算机科学的学生介绍生物学建模。该奖项由MPS数学科学部(DMS)通过数学生物学计划和分子和细胞生物科学部(MCB)通过细胞动力学和功能集群共同资助。该奖项反映了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。

Cell growth and division requires cells to polarize by forming distinct compartments with different molecular components. Faulty cell polarization contributes to birth defects or diseases such as cancer. The PI will develop stochastic and deterministic models to better understand how biochemical factors in the cell interact and regulate each other for proper cell function. This project will model the segregation of chemical reactions taking place on cell membranes and in the interior of the cell. Such segregation is thought to give rise to interesting dynamical phenomena, such as oscillations of the central polarity regulator, Cdc42, and establishment of multiple polarity zones. The effects of compartmentalization and geometry on the dynamics of polarization is just beginning to be explored and may lead to novel biological insights of how cell polarity is maintained in cells. The PI’s long term educational goal is to encourage female undergraduate and graduate students to pursue careers in STEM fields, specifically in Applied Mathematics. Broader educational impacts will involve organizing a workshop for undergraduate and graduate students at the University of Notre Dame. The PI will focus on establishment of polarity in fission yeast and budding yeast, two model organisms for understanding how cells integrate polarity and spatial coordination of growth. The current mathematical approach to modeling cell polarity using reaction-diffusion equations does not take into effect the spatial segregation of polarity molecules in the cell. The goal of this project is to model cell signaling occurring during cell polarization by coupling bulk diffusion to active surface-bound chemical species. The PI will apply this bulk- surface PDEs framework to specific scientific aims: (1) Extend the deterministic bulk-cytosol 1D model framework to a spatial stochastic one that describes the inherent noise in the underlying biochemical system, and compare model findings for increasing cell size and molecule number using compartment based SSA approach, (2) Extend the 1D framework to higher dimensions, where cortical domains are modeled as a thin patches to allow for lateral diffusion and the cytosol is modeled as an enclosed volume, and consider effects of cell geometry on intracellular signaling. The educational objectives of this proposal are: 1) organize a workshop for undergraduate women encouraging them to pursue careers in Applied Mathematics and other STEM fields, 2) participate in Women Leaders in STEM program at Notre Dame, 3) develop new materials for graduate course on Mathematical Cell Biology, which will be open to interdisciplinary students, 4) lecture in existing national educational programs such as the q-bio Summer School that introduces students from diverse disciplines such as mathematics, physics, and computer science to modeling in biology. This award is being co-funded by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program and the BIO Division of Molecular and Cellular Biosciences (MCB) through the Cellular Dynamics and Function Cluster.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.