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。 这些多方面的细胞对抗感染，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并导致神经退行性病变，如阿尔茨海默病。 这与细胞代谢的变化有关，但这种代谢重编程如何以及为什么发生及其对疾病进展的影响仍然未知。 该项目将开发和分析多尺度数学模型，以更好地了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的进一步细胞活动。 该项目将在跨学科研究技术方面纳入和培训本科生。 此外，该项目将评估本科研究经验对学生科学身份和坚持STEM的影响。 本研究的主要目标是：1）通过常微分方程建模和分析，在单个健康细胞中模拟小胶质细胞的代谢，并了解代谢与表型承诺和行为的对应关系;（二）阐明小胶质细胞和其他细胞类型之间的串扰，并通过常微分方程建模在数学上描述在炎症条件下可能发生的潜在乳酸穿梭分析;以及3）通过使用基于代理的模型来描述空间分量和单元异质性。 该项目使用的主要工具包括数值模拟、全局敏感性分析和通过使用合作者与数学工作并行进行的生物实验数据来参数化模型。 串扰和基于代理的模型将专门考虑与阿尔茨海默病相关的途径。 该项目还将通过混合方法研究评估本科生研究经验的影响，以评估学生归属感，科学自我效能感和科学身份的变化。 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NSF的法定使命，并被认为是值得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的支持。

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.