RUI: Mathematical Modeling of Microglia

小胶质细胞是一种特殊类型的免疫细胞，只在中枢神经系统中发现。这些多面细胞对抗感染、修复损伤、清除碎片，是维持大脑健康的核心。然而，这些细胞可能会失控，导致神经退行性疾病，如阿尔茨海默病。这与细胞代谢的转变有关，但这种代谢重编程发生的方式和原因及其对疾病进展的影响尚不清楚。该项目将开发和分析多尺度数学模型，以更好地理解各种分子机制在小胶质细胞行为中的作用，以及这种行为如何影响和协调大脑中进一步的细胞活动。这个项目将包括和训练本科生跨学科的研究技术。此外，该项目将评估本科生研究经历对学生科学认同和STEM坚持的影响。本项目旨在实现三个具体目标：1)在单个健康细胞中建立小胶质细胞代谢模型，并通过常微分方程建模和分析了解代谢如何对应表型承诺和行为；2)结合小胶质细胞与其他类型细胞之间的串扰，通过常微分方程建模和分析，从数学上描述炎症条件下可能发生的潜在乳酸穿梭；3)利用基于agent的模型结合空间成分和细胞异质性。该项目使用的主要工具包括数值模拟、全局敏感性分析和参数化模型，这些模型使用的是合作者在进行数学工作的同时进行的生物实验数据。串音和基于主体的模型将特别考虑与阿尔茨海默病相关的途径。本计划亦会以混合方法研究本科生科研经历的影响，以评估学生的归属感、科学自我效能感及科学认同的变化。该项目由MPS数学科学部（DMS）通过数学生物学计划和BIO分子和细胞生物科学部通过系统和合成生物学集群共同资助。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。

Microglia are a special type of immune cell found only in the central nervous system. These multifaceted cells fight infections, repair damage, remove debris, and are central to maintaining brain health. However, these cells can go rogue and contribute to neurodegenerative pathologies such as Alzheimer's Disease. This is linked to a shift in their cellular metabolism, but how and why this metabolic reprogramming occurs and its impact on disease progression remains unknown. This project will develop and analyze multi-scale mathematical models to better understand the role of various molecular mechanisms in microglia behavior and how this behavior influences and orchestrates further cellular activity in the brain. This project will incorporate and train undergraduate students in interdisciplinary research techniques. Additionally, the project will assess the impact of an undergraduate research experience on students' science identity and persistence in STEM. This project aims to accomplish three specific goals: 1) Modeling microglia metabolism in a single healthy cell and understanding how the metabolism corresponds to phenotype commitment and behavior through ordinary differential equation modeling and analysis; 2) Incorporating crosstalk between microglia and other cell types and mathematically describing a potential lactate shuttle which may occur under inflammatory conditions through ordinary differential equation modeling and analysis; and 3) Incorporating a spatial component and cell heterogeneity by using agent-based models. The primary tools to be used for this project include numerical simulation, global sensitivity analysis, and parameterizing models by using data from biological experiments conducted by collaborators in parallel with the mathematical work. Cross-talk and agent-based models will specifically consider pathways linked to Alzheimer's Disease. The project will also evaluate the impact of the undergraduate research experience with a mixed method study to assess changes in students' sense of belonging, science self-efficacy, and science identity. This project is jointly funded by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program, and the BIO Division of Molecular and Cellular Biosciences through the System and Synthetic Biology Cluster. 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.