CAREER: Connecting biology and mechanics through a multiscale modeling of pubertal mammary gland development

职业：通过青春期乳腺发育的多尺度建模将生物学和力学联系起来

• 批准号: 2240155
• 负责人: Uduak George
• 金额: $ 60.01万
• 依托单位: San Diego State University Foundation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2240155&HistoricalAwards=false
• 关键词: CAREER; Connecting; biology; mechanics; through

This research will advance our understanding of the mechanism that governs the emergence of complex biological networks. It proposes novel approaches for combining laboratory experiments and multiscale mathematical modeling to characterize branching morphogenesis in the mammary gland. Branching morphogenesis is a process by which the female mammary gland develops its tree-like structure during puberty. It governs the formation of other tree-like organs such as the lungs, salivary gland, and kidney. Defects in branching morphogenesis can lead to hypertension, chronic kidney failure, and poor lung function. Mechanisms that control branching morphogenesis are circumvented or altered during the development and progression of breast cancer. Understanding the mechanisms that generate branched organs may identify novel ways to treat breast cancer, regenerate organ function, or design artificial organs to combat diseases. At puberty, branching morphogenesis generates an extensive network of mammary gland epithelium ducts. The epithelium ductal network is connected at its base to the nipple and plays a key role in milk synthesis and secretion for neonates. Molecular and mechanical factors in the tissue environment are important for normal branching morphogenesis. Majority of the research in this area has focused on identifying key molecular factors and the mechanisms by which they regulate branching morphogenesis. How mechanical signaling regulates branching morphogenesis remains largely unknown. The mathematical models proposed in this research will contribute to bridging this gap. This project will build novel multiscale mathematical models to predict how the interactions between mechanical and cellular signaling regulate the formation of the mammary ductal network. Branching morphogenesis occurs through two stages: the first stage is via successive rounds of elongation and splitting of the tip of individual ducts (i.e., tip bifurcation) and the second stage is via budding along the sides of existing ducts (i.e., side branching). Increased extracellular matrix (ECM) stiffness is known to increase the sites for epithelium ductal branch initiation. However, how the mechanical signaling originating from the ECM affects branch elongation, tip bifurcation and side branching is not fully understood. This project will (1) combine optimal transport theory, agent-based models, and data from laboratory experiments to predict how interactions between ECM and epithelium cells regulate ductal branch elongation and tip bifurcation in the mammary gland, (2) apply topological data analysis and multifractal analysis to predict the role of tensional force and ECM stiffness on ductal tip bifurcation and side branching in the mammary gland. Findings from this research will improve our understanding of how biomechanical forces affect ductal network formation. This CAREER project will contribute to the training of undergraduate and graduate students at San Diego State University (SDSU), a Hispanic Serving Institution. It will integrate mathematical biology research activities in the undergraduate curriculum at SDSU and train students early in their career to approach scientific inquiry in a way that crosses scientific disciplines. Furthermore, this project will provide a summer workshop to guide local teachers-leaders in creating teaching modules that integrate quantitative research and foster critical thinking in high school students in high-need urban schools.This award is jointly funded by the MPS-DMS-Mathematical Biology program, BIO-MCB-Cellular Dynamics and Function program, and MPS-PHY-Physics of Living Systems (PoLS) 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.

这项研究将促进我们对控制复杂生物网络出现的机制的理解。它提出了结合实验室实验和多尺度数学模型来表征乳腺分支形态发生的新方法。分支形态发生是雌性乳腺在青春期形成树形结构的过程。它支配着其他树状器官的形成，如肺、唾液腺和肾脏。分支形态发生缺陷可导致高血压、慢性肾衰竭和肺功能不良。控制分支形态发生的机制在乳腺癌的发生和发展过程中被规避或改变。了解产生分支器官的机制可能会找到治疗乳腺癌、再生器官功能或设计人工器官来对抗疾病的新方法。在青春期，分支形态发生产生了广泛的乳腺上皮导管网络。上皮导管网在其底部与乳头相连，在新生儿的乳汁合成和分泌中起着关键作用。组织环境中的分子和力学因素对正常分支形态的形成起着重要的作用。该领域的大部分研究都集中在确定关键分子因子及其调控分支形态发生的机制上。机械信号调控分支形态发生的机制在很大程度上仍然未知。本研究提出的数学模型将有助于弥合这一差距。本项目将建立新的多尺度数学模型来预测机械信号和细胞信号之间的相互作用如何调节乳腺导管网络的形成。分支形态发生通过两个阶段：第一阶段是通过连续几轮的延伸和个别导管的尖端分裂（即，尖端分叉），第二阶段是通过沿着现有导管的侧面出芽（即，侧分支）。细胞外基质（ECM）硬度的增加增加了上皮导管支起始的位置。然而，来自ECM的机械信号如何影响分支延伸，尖端分叉和侧分支尚不完全清楚。本项目将(1)结合最优转运理论、基于主体的模型和实验室实验数据，预测ECM与上皮细胞之间的相互作用如何调节乳腺导管分支的延伸和尖端分叉；(2)应用拓扑数据分析和多重分形分析，预测张力和ECM刚度对乳腺导管尖端分叉和侧分支的作用。这项研究的发现将提高我们对生物力学力如何影响导管网络形成的理解。这个职业项目将有助于圣地亚哥州立大学（SDSU）的本科生和研究生的培训，这是一个西班牙裔服务机构。它将把数学生物学研究活动整合到SDSU的本科课程中，并在学生的职业生涯早期培养他们以跨科学学科的方式进行科学探究。此外，该项目将提供一个夏季研讨会，指导当地教师和领导者创建教学模块，整合定量研究，培养城市高需求学校高中生的批判性思维。该奖项由mps - dms -数学生物学项目、bio - mcb -细胞动力学和功能项目以及mps -物理-生命系统物理学（PoLS）项目共同资助。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。