Multiscale Modeling of Wound Healing

伤口愈合的多尺度建模

• 批准号: 8744539
• 负责人: Jason M. Haugh
• 金额: $ 50.08万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744539
• 关键词: 1,2-diacylglycerol; Actins; Actomyosin; Address; Affect; Animals; Behavior; Biological; Blood Platelets; Bypass; Cell Shape; Cells; Cellular biology; Chemotaxis; Chronic; Coagulation Process; Complex; Complication; Computer Analysis; Cutaneous; Cytoskeleton; Data; Dermal; Development; Diabetes Mellitus; Dictyostelium; Diffusion; Diglycerides; Disease; F-Actin; Feedback; Fibrin; Fibroblasts; Genetic; Geometry; Healed; Healthcare; Heterogeneity; Hour; Human; Image Analysis; Immune response; Invaded; Kinetics; Knowledge; Length; Leukocytes; Life; Link; Measurement; Mesenchymal; Microfilaments; Microfluidic Microchips; Microfluidics; Microscopy; Modeling; Molds; Molecular; Molecular Biology; Monitor; Motion; Motor Activity; Mus; Myosin ATPase; Myosin Light Chains; Myosin Regulatory Light Chains; Myosin Type II; Obesity; Outcome; Pathway interactions; Pattern; Pharmacological Treatment; Phase; Phosphorylation; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Positioning Attribute; Process; Property; Public Health; Reaction; Receptor Mediated Signal Transduction; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Speed; Stress Fibers; Structure; System; Time; Tissues; Trauma; United States; Wound Healing; biophysical model; cell behavior; cell motility; cell type; healing; in vivo; insight; intravital imaging; migration; model development; molecular scale; multi-scale modeling; non-muscle myosin; novel strategies; novel therapeutic intervention; polymerization; predictive modeling; public health relevance; self assembly; self organization; simulation; spatiotemporal; statistics; wound

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.

描述（由申请人提供）：慢性伤口是对公共健康和经济的主要威胁，并且是人类主要疾病的共存并发症。虽然皮肤伤口的正确愈合需要多种细胞类型的集体和协调行为，但决定速率的步骤是真皮成纤维细胞的募集和功能，它们通过血小板衍生生长因子的浓度梯度引导侵入伤口（PDGF）。关于 PDGF 受体和其他受体酪氨酸激酶激活的信号转导途径，人们已经了解很多。然而，关于这些通路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不断出现。更大的根本差距在于伤口愈合的分子、超分子、细胞和组织水平动力学的整合，其跨越不同的时间（秒到周）和空间（纳米到厘米）尺度。为了推进这一领域的发展，需要新的方法来融合数据相对丰富（信号传导、细胞骨架动力学）和数据相对贫乏（体内动力学）的实验和观察尺度。为此，我们建议开发伤口愈合增殖期的预测性多尺度模型，其中包括 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）体内集体细胞行为（组织尺度）。我们的合作伙伴关系结合了实验细胞生物学和生物物理建模方面的专业知识，模型开发将以生物抽象各个规模的新定量测量为指导。