Multiscale Modeling of Wound Healing

伤口愈合的多尺度建模

• 批准号: 10002331
• 负责人: Jason M. Haugh
• 金额: $ 51.36万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002331
• 关键词: Actins; Actomyosin; Address; Adhesions; Affect; Behavior; Biochemistry; Biological; Blood Platelets; Cell Shape; Cells; Cellular Morphology; Chemotactic Factors; Chemotaxis; Clinic; Coagulation Process; Complex; Complication; Computer Analysis; Cues; Cytoskeleton; Data; Dermal; Diabetes Mellitus; Disease; Extracellular Matrix; F-Actin; Fibrin; Fibroblasts; Hour; Human; Invaded; Knowledge; Length; Link; Measures; Mechanics; Mediating; Membrane; Microfluidics; Modeling; Molecular; Molecular Biology; Monitor; Movement; Myosin ATPase; Myosin Type II; Nonmuscle Myosin Type IIA; Obesity; PRKCA gene; Pathway interactions; Pattern; Platelet-Derived Growth Factor; Positioning Attribute; Process; Property; Public Health; Recombinants; Regulation; Research; Side; Signal Pathway; Signal Transduction; Skin wound healing; Source; Space Models; Structure; Surface; Surface Properties; System; Testing; Time; Tissues; Total Internal Reflection Fluorescent; Traction; Trauma; United States; Variant; Work; Wound models; biological heterogeneity; cell behavior; cell motility; cell type; chronic wound; combinatorial; comorbidity; density; experimental study; improved; in vivo; intravital imaging; live cell microscopy; macrophage; migration; molecular scale; multi-scale modeling; outcome prediction; platelet-derived growth factor BB; polymerization; receptor-mediated signaling; recruit; response; rho; stem; therapy outcome; wound; wound healing; wound treatment

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).

项目概要 慢性伤口是对公共健康的主要威胁，并且是严重伤口的共存并发症。 人类疾病。尽管皮肤伤口的正确愈合需要集体和 多种细胞类型的协调行为，关键一步是真皮的招募和功能 成纤维细胞，通过血小板衍生的化学引诱剂的梯度引导侵入伤口 生长因子（PDGF）。目前有一些生物制品，尤其是重组 PDGF-BB 批准用于治疗伤口；然而，目前的治疗方法缺乏加速伤口愈合的功效。 治愈，因此它们尚未在临床上获得关注。这些令人失望的结果 强调在组织尺度和需求上对伤口愈合动态的了解是多么的少 连接分子、细胞和组织水平过程的知识来告知和预测结果 旨在提高伤口修复速度和保真度的治疗策略。我们曾经 考虑分子（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（偏向细胞运动）、 和组织水平（伤口侵袭）动态，跨越不同的时间（秒到周）和空间 （纳米到厘米）尺度。仍然存在许多挑战。首先是缺乏机械连接的模型 方式、信号传导和细胞骨架动力学对膜突出/缩回机制的影响 细胞前沿；我们称之为分子运动问题（目标 1）。这是受我们最近的推动 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， 力学以不同的方式。这种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种空间线索，并且 因此，考虑趋化、触触和杜罗趋化（梯度 在机械硬度中）共存于伤口中的线索。初步建模工作表明 我们建议探索的另一种形式的空间偏差：细胞形状或形态趋向的影响。 第三个需求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，因此是化学引诱剂和 ECM 的焦点来源 预计密度和刚度也会随空间和时间而变化。我们参考以下关系 作为异质环境的体内巨噬细胞位置和 ECM 的动态组织 问题（目标 3）。