权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Quantitative Analysis of Mechanochemical Signaling in Wound Response

伤口反应中机械化学信号的定量分析

基本信息

批准号：
9768888
负责人：
XUEDONG LIU
金额：
$ 36.53万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768888
关键词：
Affect Biochemical Biological Biosensor Cell Communication Cells Clinical Trials Complex Coupled Development Epidermal Growth Factor Receptor Epithelial Event Feedback Fluorescence Resonance Energy Transfer Genetic Transcription Goals Growth Factor Hydrogels Investigation Kinetics MAP Kinase Gene Measurement Measures Mechanics Modeling Molecular Movement Neoplasm Metastasis Outcome Pathologic Pathway interactions Play Process Property Regulation Role Signal Transduction Skin Specific qualifier value System Systems Biology Therapeutic Tissues Traction Force Microscopy Transforming Growth Factor beta Transforming Growth Factors Wound Healing Wounds and Injuries analytical method base cell motility design experience experimental study improved in vivo insight live cell imaging mathematical model mechanical force mechanotransduction migration network architecture non-healing wounds novel programs promoter public health relevance repaired response spatiotemporal success tissue repair tool tumor progression wound

项目摘要

DESCRIPTION: Wound healing involves complex interplay between growth factors and cell-cell interactions. TGF-ß is one of the key growth factors that is known to be involved in wound healing in vivo. TGF-ß secretion coincides with the early stages of tissue repair and promotes collective cell migration. This revelation has prompted numerous clinical trials using this growth factor to treat nonhealing wounds. Despite much enthusiasm, there is not much success with its use as a wound promoter. The limited success using growth factors for wound therapies can in part be attributed to the fact that wound healing growth factors act in a concerted manner and in sequence to regulate the repair process. Limited mechanistic understanding of the spatiotemporal regulation of wound healing signaling response, coupled with the lack of quantitative modeling and analytical methods, has hampered the rational development of new improved therapeutic strategies. Our long-term goal is to develop a quantitative framework to investigate concerted action of growth factors and mechanotransduction in normal and pathological wound healing. Although the vast majority of investigations describe wound healing cellular responses to biochemical signals, it is becoming increasingly clear that mechanical force can also serve as an input for signal transduction. The objective of this application is to quantitatively assess integration of TGF-ß signaling and mechanical strain and develop a comprehensive mathematical model that is able to predict systems-level wound healing dynamics. We hypothesize: 1) TGF-ß signaling elevates the levels of TACE in migrating epithelial sheet; 2) TGF-ß promotes elevated TACE activity through local changes in mechanical interactions; 3) TGF-ß engages a positive feedback loop between EGFR signaling and TACE to sustain elevated EGFR signaling near a wound's border. We will investigate our hypothesis using a systems biology approach that integrates kinetic experiments and mathematical modeling by pursuing three specific aims: 1) Identify signaling motifs that detect the presence of a wound and control the spatially constrained activation of MAPK dynamics in response to global treatment of TGF-ß; 2) Determine the effect of mechanical force on the dynamic properties of wound response signaling by TGF-ß; 3) Dissect and characterize the mechanisms of positive feedback between TACE activity and EGFR signaling activity in motile cells. If successful, the proposed studies will provide a general framework to analyze concerted actions of growth factors and mechanical signals.