Collaborative Research: MODULUS: Data-Driven Discovery for Mechanisms of Nuclear Dynamics and Scaling

合作研究：MODULUS：数据驱动的核动力学和尺度机制发现

• 批准号: 2052636
• 负责人: Alan Lindsay
• 金额: $ 36.26万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2052636&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; Data; Driven

This award supports research on the fundamental biological question of scaling – how cells and organelles regulate size relative to the whole organism. The nucleus is a particular organelle where scaling is tightly regulated and aberrations are often hallmarks of disease. Consequently, a better understanding of these fundamental mechanisms may lead to novel treatments. The Principal Investigators (PIs) will iterate between wet-lab experiments and mathematical modeling to uncover the principles underpinning scaling in the model system Xenopus Laevis (frog). The PIs posit that the dynamics of nuclear growth and ultimately the steady-state size of the organelle depend upon multiple, interdependent processes including (i) nuclear pore complex (NPC) mediated import of soluble proteins, (ii) osmotic/oncotic pressure differences, (iii) microtubule-dependent transport of vesicular membrane building blocks, and (iv) regulated exchange between the outer nuclear membrane and the contiguous endoplasmic reticulum. Using parameter estimation and Bayesian model selection criteria, The PIs will delineate the roles played by each of these processes. The outcomes of this award will provide a framework for data driven discovery in a vast range of biological problems. This award will enable the training of the next generation of biophysical researchers who will be immersed in both theoretical and experimental environments.The PIs will determine the mechanisms of nuclear scaling using the model system X. laevis within an iterative experimental and modeling approach. On the experimental end, the PIs will combine microfluidics, photolabile hydrogels, and cell-free cytoplasmic extracts derived from X. laevis eggs. This platform enables recapitulation of nuclear assembly and growth under controlled experimental conditions in which variables such as cytoplasmic volume, cytoplasmic shape, and cytoplasmic composition can be independently modulated. To complement this experimental framework, the PIs will develop a hierarchy of mathematical models ranging from analytically tractable (single nucleus, radially symmetric), to computationally demanding (multiple interacting nuclei, complex cell geometry). These models will take the form of free boundary partial differential equations (reaction-advection-diffusion PDEs) and describe the transport of proteins by unbiased diffusion, directed motion along microtubules and active fluid flow. To incorporate surface details of the nuclear envelope, particularly the arrangement and dynamics of NPCs during nuclear growth, macroscopic laws describing rates of import and growth will be obtained using asymptotic analysis and homogenization theory. Broader impacts arising from this award include 1) cross disciplinary training of graduate students in both experimental and modeling through rotations at U. Wyoming and Notre Dame 2) two international workshops aimed at cementing connections between biological and mathematical scientists and further dissemination of research methodologies and tools.This award is being co-funded by the Division of Molecular and Cellular Biosciences (MCB) through the Systems and Synthetic Biology and the Cellular Dynamics and Function Cluster, and the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program.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.

该奖项支持对缩放的基本生物学问题的研究-细胞和细胞器如何调节相对于整个生物体的大小。细胞核是一种特殊的细胞器，它的缩放受到严格的调节，畸变通常是疾病的标志。因此，更好地了解这些基本机制可能会导致新的治疗方法。首席研究员（pi）将在湿实验室实验和数学建模之间进行迭代，以揭示模型系统Xenopus Laevis（青蛙）缩放的基础原理。pi假设核生长的动力学和细胞器的最终稳态大小取决于多个相互依赖的过程，包括(i)核孔复合物（NPC）介导的可溶性蛋白质的进口，（ii）渗透/肿瘤压差，（iii）依赖微管的囊膜构建块运输，以及（iv）外核膜和连续内质网之间的调节交换。使用参数估计和贝叶斯模型选择标准，pi将描述这些过程中每个过程所扮演的角色。该奖项的成果将为广泛的生物学问题的数据驱动发现提供一个框架。该奖项将培养下一代生物物理研究人员，他们将沉浸在理论和实验环境中。pi将在迭代实验和建模方法中使用模型系统X. laevis确定核缩放机制。在实验端，pi将结合微流体、光敏水凝胶和无细胞的细胞质萃取物，这些萃取物来源于紫斑天竺葵卵。该平台能够在可控的实验条件下重现核组装和生长，其中细胞质体积、细胞质形状和细胞质组成等变量可以独立调节。为了补充这个实验框架，pi将开发一个层次的数学模型，从易于分析的（单核，径向对称）到计算要求高的（多个相互作用的核，复杂的细胞几何）。这些模型将采用自由边界偏微分方程（反应-平流-扩散PDEs）的形式，并通过无偏扩散、沿微管定向运动和主动流体流动来描述蛋白质的运输。为了结合核包膜的表面细节，特别是核生长过程中npc的排列和动态，将使用渐近分析和均质化理论获得描述进口和增长速度的宏观规律。该奖项产生的更广泛的影响包括：1)通过在怀俄明大学和圣母大学的轮转，对研究生进行跨学科的实验和建模培训；2)两个国际研讨会旨在巩固生物学和数学科学家之间的联系，并进一步传播研究方法和工具。该奖项由分子和细胞生物科学部（MCB）通过系统和合成生物学以及细胞动力学和功能集群，以及MPS数学科学部（DMS）通过数学生物学计划共同资助。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

Mathematical modeling accurately predicts the dynamics and scaling of nuclear growth in discrete cytoplasmic volumes

数学模型准确预测离散细胞质体积中核生长的动态和缩放

• DOI: 10.1016/j.jtbi.2021.110936
• 发表时间: 2022
• 期刊: Journal of Theoretical Biology
• 影响因子: 2
• 作者: Leech, V.;Hazel, J.W.;Gatlin, J.C.;Lindsay, A.E.;Manhart, A.
• 通讯作者: Manhart, A.