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复杂生物网络出现机制的理解。它提出了新的方法，结合实验室实验和多尺度数学建模，以表征乳腺中的分支形态发生。分支形态发生是女性乳腺在青春期发育成树状结构的过程。它控制着其他树状器官的形成，如肺、唾液腺和肾。分支形态发生的缺陷可导致高血压、慢性肾衰竭和肺功能不良。在乳腺癌的发展和进展过程中，控制分支形态发生的机制被规避或改变。了解产生分支器官的机制可能会发现治疗乳腺癌，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，分支形态发生产生广泛的乳腺上皮导管网络。上皮导管网络在其基部连接到乳头，并且在新生儿的乳汁合成和分泌中起关键作用。组织环境中的分子和机械因素对于正常的分枝形态发生是重要的。在这一领域的研究主要集中在确定关键的分子因子和它们调节分枝形态发生的机制。机械信号如何调节分枝形态发生在很大程度上仍然是未知的。本研究中提出的数学模型将有助于弥合这一差距。该项目将建立新的多尺度数学模型来预测机械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。分枝形态发生通过两个阶段发生：第一阶段是通过连续轮的伸长和单个导管尖端的分裂（即，尖端分叉）而第二阶段是通过沿着现有管道的侧面出芽（即，侧支化）。 已知细胞外基质（ECM）硬度增加会增加上皮导管分支起始的位点。然而，源自ECM的机械信号传导如何影响分支伸长、尖端分叉和侧支化尚不完全清楚。本项目将（1）结合联合收割机最佳运输理论、基于代理的模型和实验室实验数据，预测ECM和上皮细胞之间的相互作用如何调节乳腺导管分支伸长和尖端分叉，（2）应用拓扑数据分析和多重分形分析来预测张力和ECM刚度对乳腺导管尖端分叉和侧支的作用。这项研究的结果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在圣地亚哥州立大学（SDSU），西班牙裔服务机构的本科生和研究生的培训。它将在SDSU的本科课程中整合数学生物学研究活动，并在职业生涯的早期培养学生以跨科学学科的方式进行科学探究。此外，该项目还将提供一个暑期研讨会，指导当地教师领导创建教学模块，将定量研究与培养批判性思维相结合，培养高需求城市学校的高中生。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，该奖项反映了NSF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。