Characterization of disrupted hematopoiesis by mathematical modelling

自从20世纪60年代在多伦多大学发现造血干细胞以来，人们对它们进行了深入的研究。因此，血液系统可能是人们最了解的干细胞分化系统。许多调节造血的多种细胞因子反馈机制已经被成功地描述出来，但我们的理解仍然存在差距。造血控制环路通常在整个生命过程中无懈可击地运行，但当这种机制被破坏时，病理性的血细胞生产可能会随之而来。需要新的和创新的方法来量化和预测维持造血的机制，并阐明血液系统对其生产中断的反应。 这项研究旨在了解和预测造血干细胞产生的动态，并阐明这些动态在动态平衡和应激性造血中所起的作用。这里的重点是通过利用对两种特定血细胞产生障碍的研究来阐明造血控制系统的中断是如何出现的，这两种疾病是克隆性造血(血液系统被单一血细胞的后代取代)和慢性炎症(先天免疫白细胞持续过剩)。 通过构建随机数学模型和年龄结构延迟微分方程模型，结合调节造血的细胞因子的药代动力学/药效学描述以及它们与不同类型血细胞的相互作用，这个跨学科平台将阐明关键的造血关系，并探索它们是如何在应激条件下进行调节的。这项工作还将把随机和延迟模型结合起来，并开发出分析和模拟它们的数学方法。与实验进展相一致，这项研究计划是了解动态平衡血细胞产生和解开扰乱的造血如何发展和维持的生物学基础。

Since their discovery at the University of Toronto in the 1960s, hematopoietic stem cells have been studied intensively. As a result, the blood system is perhaps the best understood stem cell differentiation system. Many of the multiple cytokine feedback mechanisms that regulate hematopoiesis have been successfully characterized, however gaps in our understanding remain. Hematopoietic control loops usually operate faultlessly throughout life, but pathological blood cell production can ensue when this machinery is disrupted. There is a need for new and innovative approaches to quantify and predict the mechanisms responsible for maintaining hematopoiesis, and to elucidate the response of the blood system to disruptions to its production. This research aims to understand and predict the dynamics of hematopoietic stem cell production and clarify the role these dynamics play in homeostatic and stress hematopoiesis. The focus here is to shed light on how disruptions to hematopoietic control systems emerge by leveraging research into two specific blood cell production disorders, namely clonal hematopoiesis (where the blood system is overtaken by descendants from a single blood cell) and chronic inflammation (the sustained overproduction of innate immune white blood cells). By constructing stochastic mathematical models and age-structured delay differential equation models in combination with pharmacokinetic/pharmacodynamic descriptions of the cytokines regulating hematopoiesis and their interactions with different types of blood cells, this interdisciplinary platform will elucidate key hematopoietic relationships and explore how they are modulated by stress. The work will also bring together stochastic and delay models, and develop mathematical methods for their analysis and simulation. In concert with experimental advances, this research program is foundational to understanding homeostatic blood cell production and untangling the biology of how perturbed hematopoiesis develops and is sustained.