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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：
9904471
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904471
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 Epigenetic Process 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 Polyadenylation Process 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 base chronic wound diabetic ulcer 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 therapeutics paracrine 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.

项目摘要表皮角质形成细胞通过恢复表皮屏障和分泌旁分泌因子控制着包括伤口血管生成和肌成纤维细胞功能在内的多种过程。在在致病环境中，受损的表皮功能导致慢性不足（例如，糖尿病溃疡）或过度- 旺盛的愈合（例如，增生性疤痕）。我们的长期目标是通过以下方式开发治疗范例：所述整联蛋白可被操纵以调节致病性角质形成细胞功能。虽然它是公认的整联蛋白调节增殖、迁移和生长因子信号传导，它们在协调创伤中作用角质形成细胞的功能仍然是个谜。此外，虽然正常和伤口角质形成细胞表达整合素，在体内，在解释整合素α 9 β 1丢失后，在先前的研究中进行了混淆观察，在体外使用基因确定的、病毒转导的角质形成细胞，其表达整合素β 3 β 1和/或β 9 β 1，不同的组合，我们发现，在最后一个项目期间，1999年1月发挥交叉抑制作用，创伤细胞功能和基因表达受β 3 β 1调控，包括促进创伤细胞功能的旁分泌信号。内皮细胞功能和调节基底膜组装的自分泌信号。使用基因定义了我们衍生的在表皮中表达不同组合的p13 β 1和/或p19 β 1的小鼠，我们还发现表皮中缺失层粘连蛋白911促进了伤口血管生成，并增强了层粘连蛋白912。在损伤后再生的表皮基底膜中进行处理。根据我们最近发布的研究和新的基础数据，我们现在假设，β 9 β 1交叉抑制β 3 β 1依赖性角化细胞通过抑制新的β 3 β 1-FAK-YAP/TAZ信号传导轴发挥功能。我们进一步假设该信号轴控制促进角质形成细胞伤口功能的基因表达程序，包括内皮细胞和成纤维细胞的旁分泌刺激和基底膜的自分泌调节膜组件这一假设将在三个目标中使用共培养模型的组合进行检验， qPCR阵列、蛋白质组学、PAC-seq mRNA分析、细胞生物学和定义的遗传小鼠模型。在在本项目期结束时，我们将在第一个项目期建立的基础上进一步阐明角质形成细胞中整合素信号传导下游的复杂信号传导网络，其控制旁分泌，正常伤口中的自分泌信号。我们还将确定这些整合素信号通路是如何在表皮肿瘤中改变，其中血管生成和其他伤口过程持续存在。为此，我们将已经为新型整联蛋白靶向治疗剂开发了基础，以调节角质形成细胞功能和创伤结果。