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.

项目概要/摘要 手术和受伤后伤口的正确愈合至关重要，而愈合不良则是一个问题 糖尿病、肥胖、吸烟和营养不良等疾病的因素。 愈合后的恢复是有限的，因此大多数修复会导致疤痕形成和丧失 每年有数百万人受到相关护理费用的影响，伤口受损。 愈合、慢性伤口和纤维化相关疾病是严重的健康负担。 揭示了活性氧（ROS）的存在，这是有氧代谢的副产物 含有高反应性的氧气，对伤口愈合结果也至关重要。 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。 证据是矛盾的，表明两者都是积极的（修复和免疫招募所需） 此外，尚不清楚 ROS 是否会造成损伤。 我们的初步数据表明，愈合和再生是两个独立的过程。 不同的伤口特异性和再生特异性 ROS 信号通路，并证明 涡虫在解析 ROS 在组织修复中的作用方面很有用，而所有这些都是多细胞的。 生物体具有伤口反应和修复机制，即促进愈合的信号 再生与疤痕仍然是一个谜，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，确定新的治疗目标并改进当前的疗法以改善患者的状况 该提案的目标是确定 ROS 水平的差异和切换信号。 损伤引起的ROS反应从控制伤口愈合到组织修复我们有两种。 假设：1) 不同的 ROS 引发的信号通路调节伤口愈合组织与伤口愈合组织 修复，2) 伤口部位 ROS 的水平和时间决定是否 伤口愈合或再生的发生将通过两个具体目的进行测试：AIM 1) 以确定。 仅伤口与 ROS 介导基因的再生特异性表达，检测任何上位性 相互作用；和 AIM 2) 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）。 AREA机制，这项工作设计主要由本科生完成—— 为了培养未来的独立性并培训他们常用技术（例如显微外科手术、 克隆、原位杂交、免疫组织化学和 RNA 干扰）。 我们对受损伤口愈合进展和纤维化的理解，并揭示基本原理 修复过程中如何利用 ROS 的原则。