Collaborative Research: Quantitative Principles behind the Spatio-Temporal Oscillation of Intracellular Calcium

本项目将研究细胞中的钙离子在极性细胞生长过程中有时如何在空间和时间上发生快速振荡，这是一种在植物受精过程中花粉管尖端生长、真菌菌丝延伸和肿瘤细胞转移过程中极其重要的机制。时空钙离子图像数据将从生长的拟南芥花粉管中收集，研究人员将采用迭代建模实验测试方法，利用细胞生物学家，数学家和统计学家的联合专业知识，旨在发现调节快速定向花粉管尖端生长的未知定量机制。从这个项目中获得的基本知识可能有助于化学或遗传疾病治疗策略的发展，因为细胞极化涉及许多人类疾病和癌症。 结果可以帮助了解真菌病原体，因为花粉管尖端的生长类似于侵入性真菌菌丝的生长。这个跨学科的项目涉及本科生，研究生和博士后实习生。计算和模拟工具以及理论结果将公开提供，以便更多地使用和促进这些领域的其他研究人员。该项目由数学科学部数学生物学计划、分子和细胞生物科学部细胞动力学和功能计划以及综合有机体系统生理机制和生物力学计划共同资助。钙具有广泛的生物学重要性，不仅是骨骼发育所必需的，而且是调节大量细胞过程（如极性细胞生长）的信号。细胞内钙离子振荡是一种重要的钙离子时空信号，但其调控机制尚不清楚。本计画将以拟南芥花粉管极性生长为模式系统。 实验数据表明，振荡的花粉管尖端的生长是由时空振荡的两个相互交织的关键监管机构：ROP 1 GTdR活性定位于顶端质膜（细胞边界）和尖端集中的细胞质内的钙梯度。为了定量地阐明这些相互依赖的关系和系统的时空振荡的潜在机制，我们将开发一个二维钙梯度模型来表征尖端聚焦的细胞内钙梯度和ROP 1和钙梯度的反应-扩散激活剂-抑制剂系统的形成，产生时空振荡。ROP 1和钙动力学也将在3D中制定，以阐明快速尖端生长和生长重定向之间的机制联系。拟议的研究将建立新的设计原则，强调快速时空振荡，作为一种共同的调节机制，并组织许多细胞功能的发展战略。 这项工作还将表征钙梯度和振荡产生的定量机制，这些钙梯度和振荡是所有细胞生物体中常见的钙信号，对广泛的生物系统具有重大影响。该奖项反映了NSF的法定使命，并被认为值得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来支持。

This project will study how calcium ions in cells sometimes undergo rapid oscillations in space and time during polar cell growth, a mechanism that is extremely important during pollen tube tip growth during plant fertilization, extension of fungal hyphae, and tumor cell metastasis. Spatiotemporal calcium ion image data will be collected from growing Arabidopsis pollen tubes and the investigators will undertake an iterative modeling-experimental testing approach, drawing on joint expertise from cell biologists, mathematicians and statisticians, aimed at discovering the unknown quantitative mechanisms that modulate rapid and directed pollen tube tip growth. The fundamental knowledge gained from this project may aid development for chemical or genetic disease treatment strategies, since cell polarization is involved in many human diseases and cancers. Results could assist with understanding fungal pathogens, because pollen tube tip growth is analogous to that of invasive fungal hyphae. This interdisciplinary project involves undergraduate, graduate students and postdoctoral trainees. Computational and simulation tools and theoretical results will be made publicly available to enable greater use and facilitate other researchers in these fields. This project is funded jointly by the Division of Mathematical Sciences Mathematical Biology Program, the Division of Molecular and Cellular Biosciences Cellular Dynamics and Function Program, and the Division of Integrative Organismal Systems Physiological Mechanisms and Biomechanics Program.Calcium is of broad biological importance, needed not only for bone development but also as a signal to regulate a vast number of cellular processes such as polar cell growth. Intracellular calcium oscillation provides a key spatiotemporal calcium signal, but the underlying mechanisms regulating mechanisms remain largely unknown. The proposed project will use Arabidopsis pollen tube polar growth as a model system. Experimental data suggests that oscillatory pollen tube tip growth is controlled by the spatiotemporal oscillation of two intertwined key regulators: the ROP1 GTPase activity localized to the apical plasma membrane (cell boundary) and the tip-focused calcium gradient within the cell cytoplasm. To quantitatively elucidate these interdependent relationships and the underlying mechanism for the spatiotemporal oscillation of the system, we will develop a 2D calcium gradient model to characterize the formation of tip-focused intracellular calcium gradient and a reaction-diffusion activator-inhibitor system of ROP1 and calcium gradients that generate spatiotemporal oscillations. ROP1 and calcium dynamics will also be formulated in 3D to elucidate mechanistic linkage between rapid tip growth and growth redirection. The proposed research will establish new design principles underscoring rapid spatiotemporal oscillations that serve as a common regulatory mechanism and organize developmental strategies for many cell functions. This work will also characterize the quantitative mechanisms underlying the generation of calcium gradients and oscillations that are common calcium signals in all cellular organisms, with significant impact on a broad range of biological systems.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.