ROS Signaling in Wound Healing vs Tissue Repair

伤口愈合与组织修复中的 ROS 信号传导

• 批准号: 10654242
• 负责人: Wendy Scott Beane
• 金额: $ 44.43万
• 依托单位: WESTERN MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654242
• 关键词: Actins; Affect; Automobile Driving; Biological Models; Biological Sciences; Cell Death; Cell Respiration; Cicatrix; Cloning; Complex; DNA cassette; Data; Development; Diabetes Mellitus; Disease; Dose; Endosomes; Environment; Epidermal Growth Factor Receptor; Faculty; Feedback; Fibrosis; Fostering; Future; Gene Expression; Genes; Goals; Graduate Education; Growth; Guidelines; Health; Host Defense; Hydrogen Peroxide; Immune; Immunohistochemistry; Impaired wound healing; In Situ Hybridization; Injury; Institution; Knowledge; Lead; MAP Kinase Gene; Malnutrition; Manuscripts; Mechanics; Mediating; Methods; Michigan; Microsurgery; Natural regeneration; Obesity; Operative Surgical Procedures; Organism; Outcome; Oxidative Stress; Oxygen; Patient-Focused Outcomes; Peer Review; Physiological; Planarians; Process; Proliferating; Proto-Oncogene Proteins c-akt; Publishing; RNA Interference; Reactive Oxygen Species; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Students; System; Techniques; Testing; Time; Tissue Model; Tissues; Training; Universities; Work; care costs; cell injury; chronic wound; design; experimental study; functional restoration; gene interaction; healing; improved; in vivo; inhibitor; loss of function; neuroregulation; novel therapeutics; recruit; regenerative; repaired; response; restoration; tissue regeneration; tissue repair; tobacco abuse; transcriptomics; undergraduate research; undergraduate student; wound; wound closure; wound healing; wound response

Project Summary/Abstract Proper wound healing is critical following surgery and injury, while compromised healing is a factor in diseases such as diabetes, obesity, tobacco abuse, and malnutrition. As well, tissue restoration after healing is limited, such that most repair leads to scar formation and loss of function. With millions affected and billions in associated care costs yearly, impaired wound healing, chronic wounds and fibrosis-related diseases represent a critical health burden. Data reveals that the presence of reactive oxygen species (ROS), byproducts of aerobic metabolism containing oxygen that are highly reactive, are critical to wound healing outcomes. ROS are also necessary for cell signaling and play a role in host defense and injury signaling. But the current evidence is contradictory, suggesting both positive (required for repair and immune recruitment) and negative (promoting cell damage) roles for ROS. Furthermore, it is not clear whether wound healing and regeneration are separable processes. Our preliminary data suggests that there are different wound-specific and regenerative-specific ROS signaling pathways and demonstrates the usefulness of planarians to parse the roles of ROS in tissue repair. While all multicellular organisms possess wound responses and repair mechanisms, the signaling that promotes healing and regeneration versus scarring remains a mystery. This proposal’s long term goal is to understand how ROS signaling may be manipulated to regulate both wound healing and tissue repair, identifying new targets for treatment and refining current therapies for better patient outcomes. This proposal’s objective is to identify differences in ROS levels and signaling that switch injury-induced ROS responses from control of wound healing to tissue repair. We have two hypotheses: 1) that distinct ROS-initiated signaling pathways regulate wound healing versus tissue repair, and 2) that the level and timing of ROS present at the wound site determines whether wound healing or regrowth occurs. These will be tested with two specific aims: AIM 1) to identify wound-only versus regenerative-specific expression of ROS-mediated genes, detecting any epistatic interactions; and AIM 2) to test the effects of different ROS levels on regeneration (proliferation and tissue growth) and wound healing (actin-mediated reepithelization). In alignment with the AREA mechanism, this work is designed to be completed mainly by undergraduate students—in order to foster future independence and train them in common techniques (such as microsurgery, cloning, in situ hybridization, immunohistochemistry, and RNA interference). These studies will advance our understanding of impaired wound healing and fibrosis, and uncover fundamental principles of how ROS is utilized during repair.

项目总结/摘要 适当的伤口愈合在手术和受伤后是至关重要的，而受损的愈合是一个重要的因素。 糖尿病、肥胖症、烟草滥用和营养不良等疾病的发病因素。同样，组织 愈合后的恢复是有限的，使得大多数修复导致疤痕形成和组织损伤。 功能每年有数百万人受到影响，数十亿美元的相关护理费用， 愈合、慢性伤口和与纤维化有关的疾病是严重的健康负担。数据 揭示了活性氧（ROS）的存在，有氧代谢的副产品， 含有高活性的氧，对伤口愈合结果至关重要。ROS也 它是细胞信号传导所必需的，并在宿主防御和损伤信号传导中发挥作用。但目前的 证据是矛盾的，表明两者都是积极的（需要修复和免疫招募） 和负（促进细胞损伤）作用的ROS。此外，尚不清楚伤口是否 愈合和再生是分开的过程。我们的初步数据显示， 不同的伤口特异性和再生特异性ROS信号通路，并证明了 涡虫的有用性，以解析ROS在组织修复中的作用。虽然所有多细胞 生物体具有伤口反应和修复机制，即促进愈合的信号传导 再生和疤痕仍然是个谜。该提案的长期目标是 了解如何操纵ROS信号传导来调节伤口愈合和组织 修复，确定新的治疗靶点，改进现有疗法， 成果。该提案的目的是确定ROS水平和开关信号的差异 损伤诱导的ROS反应从控制伤口愈合到组织修复。我们有两 假设：1）不同ROS启动的信号通路调节伤口愈合， 修复，和2）在伤口部位存在的ROS的水平和时间决定是否 发生伤口愈合或再生。这些测试将有两个具体目标：目的1）识别 ROS介导的基因的仅伤口表达与再生特异性表达，检测任何上位性 相互作用;和AIM 2）以测试不同ROS水平对再生（增殖）的影响 和组织生长）和伤口愈合（肌动蛋白介导的上皮再生）。与其对准 AREA机制，这项工作的设计主要是由本科生完成-在 为了培养未来的独立性并训练他们掌握常用技术（如显微外科手术， 克隆、原位杂交、免疫组织化学和RNA干扰）。这些研究将 推进我们对受损伤口愈合和纤维化的理解，并揭示基本的 在修复过程中如何使用ROS的原则。