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

该奖项支持对结垢这一基本生物学问题的研究--细胞和细胞器如何相对于整个生物体调节大小。细胞核是一种特殊的细胞器，其伸缩受到严格控制，异常通常是疾病的标志。因此，对这些基本机制的更好理解可能会导致新的治疗方法。首席调查员(PI)将在湿实验室实验和数学建模之间反复进行，以揭示支持非洲爪哇(青蛙)模型系统缩放的原理。PI假设细胞核生长的动态和最终细胞器的稳态大小依赖于多个相互依赖的过程，包括(I)核孔复合体(NPC)介导的可溶性蛋白质的输入，(Ii)渗透压/肿胀压差，(Iii)依赖于微管的囊泡膜构建块的运输，以及(Iv)外核膜和毗连的内质网之间受调控的交换。使用参数估计和贝叶斯模型选择标准，绩效指标将描述这些过程中的每一个所扮演的角色。该奖项的结果将为在广泛的生物学问题中进行数据驱动的发现提供一个框架。这一奖项将使下一代生物物理研究人员能够接受培训，他们将沉浸在理论和实验环境中。PIS将在迭代实验和建模方法中使用模型系统X.laevis来确定核尺度的机制。在实验结束时，PI将结合微流控、耐光性水凝胶和从莱维氏X.laevis卵中提取的无细胞细胞质提取物。该平台能够在受控的实验条件下重现细胞核的组装和生长，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。为了补充这一实验框架，PI将开发一系列数学模型，从分析上容易处理的(单核，径向对称的)到计算上要求很高的(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组(反应-平流-扩散偏微分方程组)的形式，描述蛋白质通过无偏扩散、沿微管定向运动和主动流体流动的传输。为了结合核包膜的表面细节，特别是在核生长过程中核祖细胞的排列和动态，将利用渐近分析和均匀化理论获得描述进口和增长速率的宏观规律。该奖项产生的广泛影响包括1)在怀俄明大学和圣母大学通过轮换对研究生进行实验和建模方面的跨学科培训2)两个旨在加强生物和数学科学家之间的联系并进一步传播研究方法和工具的国际研讨会。该项目由MPS数学科学部(DMS)通过数学生物学计划(已建立的刺激竞争研究计划(EPSCoR))联合资助，这一奖项反映了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 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.