Multiscale Modeling of Wound Healing

描述（由申请人提供）：慢性伤口是对公共卫生和经济的主要威胁，是人类主要疾病的合并症。虽然皮肤伤口的适当愈合需要多种细胞类型的集体和协调行为，但决定速度的步骤是真皮成纤维细胞的募集和功能，它们被血小板衍生生长因子（PDGF）浓度的梯度引导侵入伤口。关于PDGF受体和其他受体酪氨酸激酶激活的信号转导途径，我们已经知道了很多；然而，关于这些途径如何在空间上组织以偏向肌动蛋白细胞骨架的动力学和细胞迁移的方向性的机制见解仍在出现。一个更大的根本差距在于分子、超分子、细胞和组织水平的伤口愈合动力学的整合，这些动力学跨越不同的时间（秒到周）和空间（纳米到厘米）尺度。为了推进这一领域，需要新的方法来融合相对数据丰富（信号，细胞骨架动力学）和数据贫乏（体内动力学）的实验和观察尺度。为此，我们建议建立一个预测伤口愈合增殖期的多尺度模型，包括1)受体介导的信号转导（分子尺度），2)收缩肌动球蛋白结构的自组装（超分子尺度），3)细胞迁移的形态动力学和统计（细胞尺度），以及4)体内细胞集体行为（组织尺度）。我们的合作结合了实验细胞生物学和生物物理建模方面的专业知识，模型的开发将以生物抽象的每一个尺度的新的定量测量为指导。

DESCRIPTION (provided by applicant): Chronic wounds are a major threat to public health and the economy and present as a comorbid complication with major diseases in humans. Although the proper healing of cutaneous wounds requires collective and coordinated behaviors of multiple cell types, the rate-determining step is the recruitment and function of dermal fibroblasts, which are directed to invade the wound by a gradient in the concentration of platelet-derived growth factor (PDGF). A great deal is known about the signal transduction pathways activated by PDGF receptors and other receptor tyrosine kinases; yet mechanistic insights about how those pathways are spatially organized to bias the dynamics of the actin cytoskeleton and the directionality of cell migration are still emerging. A still larger fundamental gap lies inthe integration of molecular, supramolecular, cellular, and tissue-level dynamics of wound healing, which span disparate time (seconds to weeks) and spatial (nm to cm) scales. To advance this field, novel approaches are needed to fuse experimental and observational scales that are relatively data-rich (signaling, cytoskeletal dynamics) and data-poor (in vivo dynamics). To that end, we propose to develop a predictive, multiscale model of the proliferative phase of wound healing, incorporating 1) receptor-mediated signal transduction (molecular scale), 2) self-assembly of contractile actomyosin structures (supramolecular scale), 3) morphodynamics and statistics of cell migration (cellular scale), and 4) collective cell behavior in vivo (tissue scal). Our partnership combines expertise in experimental cell biology and biophysical modeling, and model development will be guided by new, quantitative measurements at every scale of biological abstraction.