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Cellular Integration of Information in the Detection and Response to Epithelial Damage

上皮损伤检测和反应中的细胞信息整合

基本信息

批准号：
9893174
负责人：
M. Shane Hutson
金额：
$ 21.5万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893174
关键词：
Address Adopted Animals Area Behavior Calcium Calcium Signaling Caliber Cell Culture System Cell Proliferation Cell model Cells Cellular biology Communication Conflict (Psychology)Confusion Data Detection Development Diffuse Distal Drosophila genus Epithelial Epithelial Cells Flare Frequencies Gap Junctions Genetic Genetic Transcription Hour Image Individual Knowledge Lead Literature Location MAPK8 gene Malignant Neoplasms Mechanics Mediating Membrane Modeling Molecular Organism Pathology Pathway interactions Pattern Phylogeny Process Proliferating Publishing Pupa Radial Reporting Role Running Side Signal Transduction Spatial Behavior Stereotyping System Tissues Work Wound Healing calcium indicator cell behavior cell injury experience extracellular genetic manipulation in vivo mathematical model migration millisecond programs receptor recruit repaired response skills tool wound

项目摘要

Project Summary When an epithelial tissue is wounded, the first cellular response is a dramatic increase in cytosolic calcium levels, beginning immediately upon tissue damaged. This calcium increase is observed not just in cells at the wound margin but in large domain of cells surrounding the wound. With the advent of genetically encoded calcium indicators like GCaMP, this wound-induced calcium response has been observed in living organisms across the animal kingdom, yet conflicting mechanisms have been proposed to explain the induction of calcium, such that there is no sense of a conserved fundamental process. Our collaborative team of biophysicists and developmental geneticists recently published work identifying a major underlying obstacle: there are several contemporaneous mechanisms underlying the wound-induced calcium response, which we have been able to tease apart with our combination of highly quantitative approaches and our genetic manipulations. Without understanding the multiple mechanisms inducing calcium responses, it has been impossible to draw parallels across the literature and across wounding models, and it has impossible to fully block calcium responses to analyze the downstream consequences for wound healing. Our analysis tools identified stereotyped calcium responses, with different oscillatory patterns or signatures evident at different radial distances from the wound. We hypothesize that these patterned calcium responses inform the cell about its distance from the wound and determine its downstream cell behaviors. Like the calcium responses, wound-induced cell behaviors and transcriptional identities are patterned according to distance from the wound, with migratory cells and JNK signaling near the margin and proliferative cells and JAK-STAT signaling in a more distal ring. In the first Aim, we investigate the mechanisms of how calcium signaling is initiated in each of these patterns, working both with individual pathways and developing mathematical models for how these calcium patterns are integrated. In the second Aim, we perturb specific aspects of calcium patterns and ask how downstream cell behavior and identity are altered. We are able to achieve these Aims because of our unique collaborative skill-set, and because we have developed an unparalleled wounding model that allows genetic manipulation with high temporal control on one side of the wound only. Because it is internally controlled, comparing the two sides allows precise quantification and detection of even small changes, in both calcium signaling and wound-induced cell behaviors. At the completion of this project, we expect to have generated a high-precision model of how cells detect tissue damage at a distance, and how they interpret this information to select a spatially-appropriate repair program. This fundamental knowledge will be important to many areas of cell biology, to wound-healing studies, and to pathologies like cancer where wound-healing programs are inappropriately activated.

项目总结