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: 2052640
• 负责人: Jesse Gatlin
• 金额: $ 37.58万
• 依托单位: University of Wyoming
• 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=2052640&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; Data; Driven; 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 project is jointly funded by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program, the Established Program to Stimulate Competitive Research (EPSCoR), and the Division of Molecular and Cellular Biosciences (MCB) through the Systems and Synthetic 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.

该奖项支持有关扩展基本生物学问题的研究 - 细胞和细胞器如何相对于整个组织调节大小。核是一个特定的细胞器，尺度受到严格调节，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。主要研究人员（PIS）将在湿的实验和数学建模之间进行迭代，以发现模型系统Xenopus laevis（Frog）中的原理。 PI指出，核生长的动力学以及最终的细胞器稳态大小取决于多个相互依存的过程，包括（i）核孔复合物（NPC）介导的固体蛋白的进口，（ii）渗透/肿瘤压力差异，（III）核心膜建筑块和（iii）的核心膜建筑块和（III）的核心循环（III）的交换（III）内质网。使用参数估计和贝叶斯模型选择标准，PI将描述每个过程中每个过程所扮演的角色。该奖项的结果将为数据驱动的发现提供一个框架，这些发现在广泛的生物学问题中。该奖项将使下一代生物物理研究人员培训将融入理论和实验环境中。PIS将在迭代实验和建模方法中使用模型系统X. Laevis确定核缩放的机制。在实验端，PIS将结合微流体，光值水凝胶和无细胞的细胞质提取物，这些细胞质提取物源自X. laevis卵。该平台可以在受控的实验条件下概括核装配和生长，其中变量（例如细胞质体积，细胞质形状和细胞质组成）可以独立调节。为了补充这一实验框架，PIS将开发出数学模型的层次结构，从分析可拖动（单核，径向对称）到计算要求（多重相互作用的核，复杂细胞几何形状）。这些模型将采用自由边界偏微分方程（反应 - 添加扩散PDE）的形式，并通过无偏扩散，沿微管的定向运动和活动流体流动来描述蛋白质的传输。为了结合核包膜的表面细节，尤其是核生长过程中NPC的排列和动力学，将使用不对称分析和均质化理论获得描述进口和生长速率的宏观定律。 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 methods and tools.This project is jointly funded by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program, the Established Program to Stimulate竞争性研究（EPSCOR），以及通过系统和合成生物学计划的分子和细胞生物科学（MCB）划分。该奖项反映了NSF的法定任务，并通过使用基金会的智力优点和更广泛的影响来评估NSF的法定任务。