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

这个项目将研究细胞中的钙离子在极地细胞生长过程中有时如何在空间和时间上经历快速振荡，这一机制在植物受精期间花粉管顶端的生长、真菌菌丝的伸展和肿瘤细胞的转移过程中非常重要。将从正在生长的拟南芥花粉管中收集时空钙离子图像数据，研究人员将采用迭代建模-实验测试的方法，利用细胞生物学家、数学家和统计学家的联合专业知识，旨在发现调节花粉管顶端快速和定向生长的未知数量机制。从这个项目中获得的基本知识可能有助于开发化学或遗传疾病治疗策略，因为细胞极化与许多人类疾病和癌症有关。结果可能有助于理解真菌病原体，因为花粉管顶端的生长类似于入侵真菌菌丝的生长。这个跨学科项目涉及本科生、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之于众，以便更广泛地使用，并为这些领域的其他研究人员提供便利。本项目由数学科学数学生物学学部、分子与细胞生物科学学部、细胞动力学与功能学部、综合组织系统生理机制与生物力学学部共同资助。钙具有广泛的生物学意义，不仅是骨骼发育所必需的，也是调控极地细胞生长等多种细胞过程的信号。细胞内钙振荡提供了一个关键的时空钙信号，但其潜在的调控机制在很大程度上仍不清楚。拟建项目将以拟南芥花粉管极地生长为模式系统。实验数据表明，振荡的花粉管顶端生长受两个相互交织的关键调控因子的时空振荡控制：定位于顶端质膜(细胞边界)的ROP1 GTP酶活性和细胞质内聚焦于顶端的钙梯度。为了定量地阐明这些相互依赖的关系和系统时空振荡的潜在机制，我们将建立一个2D钙梯度模型来表征以尖端为中心的细胞内钙梯度的形成，以及ROP1和产生时空振荡的钙梯度的反应-扩散激活-抑制系统。ROP1和钙动力学也将以3D形式表达，以阐明尖端快速生长和生长重定向之间的机制联系。这项拟议的研究将建立新的设计原则，强调作为共同调节机制的快速时空振荡，并组织许多细胞功能的发展战略。这项工作还将描述钙梯度和振荡产生的量化机制，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。

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.