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).

项目摘要 慢性伤口是对公共卫生的主要威胁，并作为合并症并发症与主要的并发症 人类疾病。尽管皮肤伤口的适当愈合需要集体和 多种细胞类型的协调行为，一个关键的步骤是真皮的募集和功能 成纤维细胞指示通过趋化剂，血小板衍生的梯度侵入伤口 生长因子（PDGF）。少数几个生物学，最著名的是重组PDGF-BB，目前是 批准治疗伤口；但是，目前的治疗缺乏加速伤口的功效 康复，因此他们没有在诊所获得关注。这些令人失望的结果 强调在组织量表和需求中了解伤口愈合的动力学多么差 连接分子，细胞和组织级过程的知识，以告知和预测结果 旨在提高伤口修复率和保真度的治疗策略。我们去过 通过考虑分子的考虑（信号极化）开发成纤维细胞趋化的模型 转导），超分子（肌动球蛋白结构的组装），细胞（偏置细胞运动）， 和组织级（伤口侵袭）动力学，跨越不同的时间（秒至周）和空间 （nm至cm）鳞片。仍然存在许多挑战。首先是缺乏连接的模型 方式，信号传导和细胞骨架动力学，以膜突出/缩回的力学 牢房的前沿；我们将其称为运动问题分子（AIM 1）。这是我们最近的动机 发现PDGF趋化性和迁移被细胞外基质梯度偏差（ECM）的发现 密度（触觉）由影响F-肌动蛋白动力学的不同信号通路和 机械以不同的方式。这种基本差异与第二个关键需求有关，我们 调用提示问题的多样性（AIM 2）。 PDGF只是一个空间提示，用于成纤维细胞迁移，而 因此，考虑趋化，触觉和杜罗氏术的汇合（梯度）至关重要（梯度 在机械刚度中）在伤口中共存的线索。初步建模工作暗示了 我们建议探索的其他空间偏差形式：细胞形状或形态的影响。 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，因此是趋化剂的焦点，ECM 密度和刚度也有望在空间和时间上有所不同。我们指的是 巨噬细胞位置和ECM在体内的动态组织为异质环境 问题（目标3）。