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组分的不同隔室来实现。胎儿细胞极化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子如何相互作用和相互调节，以实现适当的细胞功能。该项目将模拟细胞膜上和细胞内部发生的化学反应的分离。 这种分离被认为会引起有趣的动力学现象，如中央极性调节器Cdc 42的振荡和多极性区的建立。 分区和几何结构对极化动力学的影响才刚刚开始探索，可能会导致新的生物学见解细胞极性是如何保持在细胞中。PI的长期教育目标是鼓励女本科生和研究生在STEM领域，特别是应用数学领域从事职业。 更广泛的教育影响将涉及在圣母大学为本科生和研究生举办一个讲习班。PI将专注于在分裂酵母和芽殖酵母中建立极性，这两种模式生物用于理解细胞如何整合极性和空间生长协调。目前使用反应扩散方程来建模细胞极性的数学方法没有考虑细胞中极性分子的空间分离。 本项目的目标是通过将体扩散耦合到活性表面结合的化学物质来模拟细胞极化过程中发生的细胞信号。主要研究者将把这种体表面偏微分方程框架应用于具体的科学目标：（1）将确定性本体-胞质溶胶1D模型框架扩展到描述潜在生化系统中的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发现，（2）将1D框架扩展到更高维度，其中皮质域被建模为薄的补丁以允许侧向扩散，并且胞质溶胶被建模为封闭体积，并且考虑细胞几何形状对细胞内信号传导的影响。这项建议的教育目标是：1）为本科女生组织一个讲习班，鼓励她们从事应用数学和其他STEM领域的职业，2）参加圣母大学STEM项目的女性领导人，3）为数学细胞生物学研究生课程开发新材料，该课程将向跨学科学生开放，4）在现有的国家教育计划中进行讲座，如q-bio暑期学校，该学校向来自数学，物理和计算机科学等不同学科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BIO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。

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.