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Mechanoregulation of Basal Keratinocyte Migration in Wounded Tissue

受伤组织中基底角质形成细胞迁移的机械调节

基本信息

批准号：
10505700
负责人：
Adam Horn
金额：
$ 10万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10505700
关键词：
Acute Address Adhesions Animal Model Architecture Behavior Biophysics Bulla Calcium Signaling Cell Adhesion Cells Chronic Cicatrix Complex Cytoskeleton Defect Disease Ensure Environment Epidermolysis Bullosa Epithelial Epithelial Cells Equilibrium Extracellular Matrix F-Actin Failure Focal Adhesions Functional disorder Homeostasis Image Imaging Techniques Injury Lead Link Mechanics Mediating Membrane Minor Modeling Molecular Genetics Movement Normal Cell Optics Pathology Patients Phase Phenotype Piezo 1 ion channel Process Regulation Regulatory Pathway Research Role Signal Transduction Site Stretching Swelling Syndrome Testing Therapeutic Time Tissues Training Translating Trauma patient Universities Wisconsin Zebrafish cell behavior chronic wound epithelial injury epithelial wound experimental study fluorescence lifetime imaging healing in vivo in vivo imaging insight intravital imaging keratinocyte knock-down mechanical force mechanical signal mechanotransduction migration non-healing wounds novel prevent repaired response response to injury restoration second harmonic generation imaging skin disorder success tool wound wound closure wound healing

项目摘要

Project Summary Epithelial homeostasis is maintained by the balance of mechanical forces acting upon cells across the tissue- scale. Injury disrupts this mechanical balance and it is unclear how changing homeostatic mechanical signals impacts cell behavior needed for wound repair. Failure to efficiently repair can lead to fibrotic scarring, chronic non-healing wounds, and contribute to pathology. Epithelial wound repair relies on the migration of basal keratinocytes to the site of damage. While it is known that basal keratinocytes are sensitive to mechanical forces, we lack an understanding of how epithelial injury alters tissue mechanics in vivo and how these wound-induced biophysical changes subsequently coordinate basal keratinocyte behavior needed for wound repair. This study aims to address these issues by using larval zebrafish, which are amenable to real-time, intravital imaging due to their optical transparency. Preliminary live-imaging experiments show that epithelial injury causes rapid basal keratinocyte migration to the wound site, which is needed for efficient repair. Basal keratinocyte migration is dependent on mechanical signals, such as membrane tension due to cell swelling, and is associated with a transient and localized disruption of epithelial tissue architecture at the wound edge. Basal keratinocyte migration can be inhibited by blocking Arp2/3 complex activation or through Talin1 knockdown, suggesting a potential link between mechanical signaling and F-actin or focal adhesion complex remodeling in vivo. Further, transiently weakening cell adhesion to the extracellular matrix alters basal keratinocyte migration, causing poor wound healing, and resulting in chronic disruption of epithelial architecture. This phenotype mimics pathology associated with Kindler Syndrome, a skin disease in which patients show wound healing defects in response to injury. These preliminary observations demonstrate that basal keratinocytes of larval zebrafish respond to mechanical signals in epithelial tissue after injury by initiating a migratory response that is required for efficient wound healing. They also suggest that defective basal keratinocyte migration may contribute to wound healing pathology. The proposed study will investigate how tension sensing by the mechanotransducers Piezo1 and Talin1 regulate wound-induced basal keratinocyte behavior by F-actin and focal adhesion remodeling, respectively. These findings will subsequently be translated to investigate a zebrafish model of Kindler Syndrome to determine the contribution of dysregulated basal keratinocyte behavior to wound healing pathophysiology. To ensure the success of this project, a tailored training plan has been developed that takes advantage of the excellent research environment at the University of Wisconsin – Madison. Dedicated training in the use of the zebrafish model organism for wound healing studies and advanced in vivo imaging techniques for quantifying epithelial tissue mechanics will aid in the completion of the stated aims. This training will facilitate a successful transition to research independence.

项目总结