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Keratinocyte Integrin Crosstalk During Wound Healing.

伤口愈合过程中角质形成细胞整合素串扰。

基本信息

批准号：
10594981
负责人：
C. Michael DiPersio
金额：
$ 46.62万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594981
关键词：
Adhesions Autocrine Communication Basement membrane Candidate Disease Gene Cell Surface Receptors Cell physiology Cells Cellular biology Chronic Coculture Techniques Communication Complement Complex DNA Methylation Data Dermis Development Endothelial Cells Epidermis Extracellular Matrix Fibroblasts Foundations Gelatinase B Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Grant Growth Factor Hypertrophic Cicatrix Impairment In Situ Hybridization In Vitro Injury Integrin Binding Integrin Signaling Pathway Integrin alpha3beta1 Integrins Knockout Mice Laminin Ligands Mediating Messenger RNA Modeling Mus Myofibroblast Natural regeneration Outcome PTK2 gene Paracrine Communication Pathogenicity Pathology Pathway interactions Peptide Hydrolases Pharmacotherapy Physiological Play Poly A Polyadenylation Process Proliferating Proteins Proteomics Publishing RNase protection assay Receptor Signaling Regulation Role Signal Pathway Signal Transduction Skin Skin Neoplasms Testing Therapeutic Transgenic Organisms Variant Viral Work adhesion receptor angiogenesis autocrine chronic wound diabetic ulcer epigenetic silencing fibulin 2 gene repression healing in vivo in vivo Model integrin alpha9 beta1 keratinocyte mRNA sequencing membrane assembly migration mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention paracrine posttranscriptional procollagen C-endopeptidase programs receptor skin barrier targeted treatment tumor tumorigenesis tumorigenic wound wound epidermis wound healing wound treatment

项目摘要

PROJECT SUMMARY Epidermal keratinocytes are vital to normal wound healing by restoring the epidermal barrier and secreting paracrine factors that govern diverse processes including wound angiogenesis and myofibroblast function. In pathogenic settings, impaired epidermal function results in chronically insufficient (e.g., diabetic ulcers) or over- exuberant healing (e.g., hypertrophic scars). Our long-term goal is to develop therapeutic paradigms through which integrins can be manipulated to modulate pathogenic keratinocyte function. While it is well established that integrins regulate proliferation, migration and growth factor signaling, their roles in orchestrating wound keratinocyte functions remain enigmatic. Moreover, while normal and wound keratinocytes express integrin 91, in vivo, upon explanation integrin 91 is lost, confounding observations made in previous studies, in vitro. Using genetically defined, virally transduced keratinocytes that express integrins 31 and/or 91 in different combinations, we discovered in the last project period that 91 exerts a cross-suppressive effect on wound cell function and gene expression that is governed by 31, including paracrine signals that promote endothelial cell function and autocrine signals that regulate basement membrane assembly. Using genetically defined mice that we have derived expressing different combinations of 31 and/or 91 in the epidermis, we also found that deletion of 91 from epidermis promoted wound angiogenesis and enhanced laminin 2 processing in the regenerating, epidermal basement membrane after injury. Based on our recently published studies and new foundation data, we now hypothesize that 91 cross-suppresses 31-dependent keratinocyte functions through inhibition of a novel 31-FAK-YAP/TAZ signaling axis. We further hypothesize that this signaling axis controls a gene expression program that promotes keratinocyte wound functions, including paracrine stimulation of endothelial cells and fibroblasts and autocrine regulation of basement membrane assembly. This hypothesis will be tested in three Aims using a combination of co-culture models, qPCR arrays, proteomics, PAC-seq mRNA analysis, cell biology, and defined genetic mouse models. At the end of this project period, we will have built on the foundation developed in the first project period to elucidate the complex signaling network downstream of integrin signaling in keratinocytes that governs paracrine and autocrine signaling in normal wounds. We will also have determined how these integrin signaling pathways are altered in epidermal tumors in which angiogenesis and other wound processes persist. In doing so, we will have developed the basis for novel integrin targeting therapeutics to modulate keratinocyte function and wound outcome.

项目总结