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Multiscale Modeling of Wound Healing

伤口愈合的多尺度建模

基本信息

批准号：
10251888
负责人：
Jason M. Haugh
金额：
$ 50.33万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251888
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

项目摘要

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).

项目总结

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GMFβ controls branched actin content and lamellipodial retraction in fibroblasts.

DOI：
10.1083/jcb.201501094
发表时间：
2015-06-22
期刊：
The Journal of cell biology
影响因子：
0
作者：
Haynes EM;Asokan SB;King SJ;Johnson HE;Haugh JM;Bear JE
通讯作者：
Bear JE

Mesenchymal chemotaxis requires selective inactivation of myosin II at the leading edge via a noncanonical PLCγ/PKCα pathway.

DOI：
10.1016/j.devcel.2014.10.024
发表时间：
2014-12-22
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Asokan, Sreeja B.;Johnson, Heath E.;Rahman, Anisur;King, Samantha J.;Rotty, Jeremy D.;Lebedeva, Irina P.;Haugh, Jason M.;Bear, James E.
通讯作者：
Bear, James E.

Semi-autonomous wound invasion via matrix-deposited, haptotactic cues.

通过基质沉积的触觉提示进行半自主伤口侵袭。