The Influence of Multi-Scale Dynamics on Physical and Behavioral Cellular Patterns

多尺度动力学对身体和行为细胞模式的影响

• 批准号: RGPIN-2022-03924
• 负责人: Gasior, Kelsey
• 金额: $ 1.38万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=759204
• 关键词: Influence; Multi; Scale; Dynamics; Physical

Physical, observable patterns and repeated patterns of behavior are vital for cellular function. Such patterns occur at scales ranging from the intracellular to the tissue level. Disruption or misuse of these patterns can have devastating consequences for human health as it can lead to amyotrophic lateral sclerosis (ALS), Alzheimer's, or metastatic cancer. The overarching aim of my research program is to leverage novel mathematical modeling, numerical simulations, sensitivity analysis, and an interdisciplinary approach to investigate how vitally important small- and large-scale interactions are for maintaining cellular patterns and function. In particular, I will examine the link between different scales in three unique biological settings. Liquid-liquid phase separation (LLPS) provides an excellent environment to mathematically study how the formation of membrane-less compartments alter the molecular dynamics that occur within the cellular environment. My work on the epithelial mesenchymal transition (EMT) will use an interdisciplinary approach to focus on how complicated single-molecule dynamics and intracellular signaling cascades are involved in changes to behavioral patterns, such as metastasis. While these two model systems are seemingly disparate, they actually provide the perfect environment to develop the novel mathematical tools and biological understanding necessary to explore multi-scale patterning dynamics in both embryogenesis and the tumor environment via the differential adhesion hypothesis (DAH). Proposed over 50 years ago, the DAH suggests that different cell populations de-mix from each other in a manner similar to liquid-like de-mixing to form new embryonic compartments. Research into LLPS will develop the mathematical tools necessary to understand how cells are rearranging themselves in the embryo while the study of intracellular dynamics with EMT will further the understanding of how transmembrane proteins that prevent cellular movement, such as E-cadherin, are affected during this liquid-like cellular movement. By coupling these novel mathematical approaches with biological experiments, my work exists at the cutting edge of biomathematics and provides a truly novel approach to understanding how multi-scale patterns emerge in the cellular environment and, potentially, how they are exploited by disease.

物理的、可观察的模式和重复的行为模式对细胞功能至关重要。这种模式发生在从细胞内到组织水平的尺度上。这些模式的破坏或滥用可能对人类健康造成破坏性后果，因为它可能导致肌萎缩侧索硬化症（ALS），阿尔茨海默氏症或转移性癌症。我的研究计划的总体目标是利用新的数学建模，数值模拟，敏感性分析和跨学科的方法来研究如何至关重要的小规模和大规模的相互作用是为了维持细胞的模式和功能。特别是，我将在三个独特的生物环境中研究不同尺度之间的联系。液-液相分离（LLPS）提供了一个极好的环境，以数学研究无膜区室的形成如何改变细胞环境中发生的分子动力学。我在上皮间质转化（EMT）方面的工作将采用跨学科的方法，重点关注复杂的单分子动力学和细胞内信号级联如何参与行为模式的变化，如转移。虽然这两个模型系统看起来是不同的，但它们实际上提供了一个完美的环境来开发新的数学工具和生物学理解，这些工具和生物学理解是通过差异粘附假说（DAH）探索胚胎发生和肿瘤环境中的多尺度模式动力学所必需的。DAH在50多年前提出，它表明不同的细胞群以类似于液体的方式相互分离，以形成新的胚胎隔室。对LLPS的研究将开发必要的数学工具，以了解细胞如何在胚胎中重新排列自己，而EMT细胞内动力学的研究将进一步了解如何防止细胞运动的跨膜蛋白，如E-钙粘蛋白，在这种液体样细胞运动中受到影响。通过将这些新颖的数学方法与生物实验相结合，我的工作处于生物数学的前沿，并提供了一种真正新颖的方法来理解多尺度模式如何在细胞环境中出现，以及它们如何被疾病利用。