Multiscale Modeling of Wound Healing

项目摘要 慢性伤口是对公共健康的主要威胁，并且作为主要并发症的共病并发症存在。 人类的疾病。虽然皮肤伤口的适当愈合需要集体和 在多种细胞类型的协调行为中，关键的一步是真皮细胞的募集和功能。 成纤维细胞，其通过化学引诱物、血小板衍生的 生长因子（PDGF）。一些生物制剂，最值得注意的是重组PDGF-BB，目前正在开发中。 被批准用于治疗伤口;然而，目前的治疗在加速伤口愈合方面缺乏功效。 愈合，因此他们没有在诊所获得牵引。这些令人失望的结果 强调了在组织尺度上对伤口愈合动力学的理解是多么的贫乏， 将分子、细胞和组织水平过程的知识联系起来，以告知和预测结果 旨在提高伤口修复的速度和保真度的治疗策略。我们一直 考虑到分子（信号极化），开发成纤维细胞趋化性模型 转导），超分子（肌动球蛋白结构的组装），细胞（偏向的细胞运动）， 和组织水平（伤口侵入）动态，其跨越不同的时间（数秒至数周）和空间 (nm至cm）刻度。许多挑战依然存在。首先是缺乏一个模型连接，在一个机械的 的方式，信号和细胞骨架动力学的机制，膜突出/收缩在 细胞的前沿;我们称之为分子运动问题（目标1）。它的动机是我们最近 发现PDGF趋化性和迁移受细胞外基质（ECM）梯度的影响， 密度（趋触性）由影响F-肌动蛋白动力学的不同信号通路控制， 机械以不同的方式这一根本区别与第二个关键需求有关， 我们称之为线索多样性问题（目标2）。PDGF只是成纤维细胞迁移的一个空间线索， 因此，考虑趋化性、趋触性和趋硬性（梯度）的汇合是至关重要的 在机械硬度中）在伤口中共存的线索。初步的建模工作表明， 我们打算探索的另一种空间偏差形式：细胞形状或形态趋性的影响。 第三个需要是整合有关伤口的空间和生物异质性的信息。 快速移动的巨噬细胞分泌PDGF，因此是化学引诱物和ECM的焦点来源。 密度和刚度也预期在空间和时间上变化。我们指的是 巨噬细胞的位置和ECM的动态组织在体内作为异质环境 问题（目标3）。

PROJECT SUMMARY Chronic wounds are a major threat to public health 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, a critical step is the recruitment and function of dermal fibroblasts, which are directed to invade the wound by gradients of a chemoattractant, platelet-derived growth factor (PDGF). A handful of biologicals, most notably recombinant PDGF-BB, are currently approved for treatment of wounds; however, the current treatments lack efficacy in accelerating wound healing, and consequently they have not gained traction in the clinic. These disappointing results underscore how poorly the dynamics of wound healing are understood at the tissue scale and the need to connect knowledge of molecular, cellular, and tissue-level processes to inform and predict outcomes of therapeutic strategies aimed at improving the rate and fidelity of wound repair. We have been developing models of fibroblast chemotaxis with consideration of molecular (polarization of signal transduction), supramolecular (assembly of actomyosin structures), cellular (biased cell movement), and tissue-level (wound invasion) dynamics, which span disparate time (seconds to weeks) and spatial (nm to cm) scales. Many challenges remain. First is the lack of a model connecting, in a mechanistic way, signaling and cytoskeletal dynamics to the mechanics of membrane protrusion/retraction at the cell's leading edge; we call this the molecules to motility problem (Aim 1). It is motivated by our recent discoveries that PDGF chemotaxis and migration biased by gradients of extracellular matrix (ECM) density (haptotaxis) are governed by distinct signaling pathways that affect F-actin dynamics and mechanics in different ways. This fundamental difference is tied to the second critical need, which we call the diversity of cues problem (Aim 2). PDGF is only one spatial cue for fibroblast migration, and hence it is paramount to consider the confluence of chemotactic, haptotactic, and durotactic (gradients in mechanical stiffness) cues that coexist in wounds. Preliminary modeling work has implicated an additional form of spatial bias that we propose to explore: the influence of cell shape, or morphotaxis. The third need is to integrate information about the spatial and biological heterogeneity of the wound. Fast-moving macrophages secrete PDGF and are thus focal sources of chemoattractant, and ECM density and stiffness are also expected to vary in space and time. We refer to the relation of macrophage positions and the dynamic organization of ECM in vivo as the heterogeneous milieu problem (Aim 3).