Chemical and Physical Mechanisms of Wound Detection

伤口检测的化学和物理机制

• 批准号: 10400094
• 负责人: Philipp Michael Niethammer
• 金额: $ 70.8万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400094
• 关键词: Acute; Animals; Arachidonic Acids; Area; Biological; Biology; Biophysics; Bone Regeneration; Cells; Chemicals; Chronic; Detection; Diffuse; Disease; Epithelial; Failure; Funding; Growth Factor; Hydrogen Peroxide; Image Analysis; Immune system; Infection; Inflammation; Inflammatory Response; Injury; Leukocytes; Malignant Neoplasms; Mammals; Mediating; Medical; Molecular; Natural regeneration; Nuclear Envelope; Organism; Pathway interactions; Process; Resolution; Scheme; Signal Transduction; Tissues; Vision; Work; Wound Infection; Wound models; Zebrafish; animal tissue; cytokine; extracellular; flexibility; healing; interdisciplinary approach; interest; intravital imaging; mathematical model; mechanotransduction; novel therapeutic intervention; novel therapeutics; rapid detection; real-time images; repaired; response; response to injury; skin fibrosis; wound; wound closure; wound healing; wound response

Project Summary Rapid detection and response to injury is essential for the survival of all organisms. In animals, wounded tissues must quickly heal and locally regenerate. Failure in wound detection causes acute and chronic conditions ranging from poorly healing wounds and infections to chronically inflamed skins, fibrosis and cancer. Although the exe- cution mechanisms of wound healing (involving cytokines, growth factors, etc.) have been extensively studied, its initiation mechanisms remain little understood. My vision is to develop a genetically and physically plau- sible model of wound detection. There is a fundamental gap in understanding of how wounds are initially detected, and how the first wound signals rapidly transmit information on injury over tissue-scale dis- tances to faraway leukocytes, epithelial, and other cells that participate in healing. I study wound detection in live zebrafish whose wound responses and immune system resemble those of mam- mals yet are better amenable to high-resolution, real-time imaging at high animal throughputs. To this end, my lab combines quantitative intravital imaging with unbiased computational image analysis and various interdisci- plinary approaches ranging from biophysics to mathematical modeling. Over a decade, I have identified three chemical and one physical wound signals: hydrogen peroxide (H2O2), extracellular ATP (eATP), arachidonic acid (AA), and nuclear membrane tension. These discoveries triggered new activity in an old field. Yet, critical mech- anistic gaps remain: How is eATP sensed to mediate rapid wound closure, and how does it instruct faraway cells although it is rapidly broken down in the tissue and cannot diffuse far from a wound? How are H2O2 and AA signals integrated to mediate rapid inflammatory responses to wounds? Wound signals cause inflammation- do they also resolve it? How is wound mechanotransduction regulated on the molecular and cell biological level? These questions are of high basic biological interest, and the pathways they concern are major disease regula- tors. Answering them over the next five years can pave way for novel therapeutic approaches. My work on wound signaling has opened the door to other areas of biology where analogous mechanisms may drive medically important processes, such as infection responses, cancer and bone regeneration/remodeling. Although the primary focus of my group will remain on early wound signaling, I plan to explore some of these new areas, taking advantage of the R35’s flexible funding scheme.

项目总结