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Pro-resolving lipid mediators in immunity and vascular biology

免疫和血管生物学中的促溶解脂质介质

基本信息

批准号：
10424510
负责人：
Matthew R Spite
金额：
$ 52.46万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424510
关键词：
Acute Adhesions Agonist Anti-Inflammatory Agents Biology Blood Vessels Cardiovascular Diseases Cells Chemotaxis Chronic Clinical Complication Diabetic mouse Diet Disease Dopamine D2 Receptor Ear Edema Epidemic Epithelial Fibrosis Functional disorder GPR18 receptor Genetic Genetic Transcription Glucose Health Host Defense Immune Immunity Immunosuppression Impaired wound healing Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Interruption Lead Leukocytes LoxP-flanked allele Lymph Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic clearance Lymphatic function Lymphedema Mediating Mediator of activation protein Metabolic Diseases Metabolism Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Normal tissue morphology Obese Mice Obesity Pathway interactions Phagocytes Phenotype Play Process Production Research Resolution Role Signal Pathway Signal Transduction Small Interfering RNA Source Stress Testing Therapeutic Time Tissues Wound models acute wound base cell type cellular targeting chronic inflammatory disease cytokine diabetic ulcer draining lymph node healing immune clearance improved in vivo injured knock-down lipid mediator lymphatic dysfunction lymphatic vessel macrophage migration novel novel strategies novel therapeutic intervention programs receptor reparative process response to injury skin wound tissue injury tissue regeneration tissue repair transcriptome sequencing wound wound closure wound healing

项目摘要

Project Summary/Abstract Impaired wound healing is a prominent clinical manifestation of chronic inflammatory diseases, such as obesity and type 2 diabetes (T2D). Acute wounds in individuals with T2D can become chronic and this is associated with sustained accumulation of pro-inflammatory leukocytes, prolonged edema, and fibrosis, leading to impaired wound closure (i.e. re-epithelialization). Functional lymphatic vessels are required for clearance of immune cells, edema, and host-defense, and several lines of evidence indicate that lymphatic clearance mechanisms are impaired in obesity and T2D. However, there are no current strategies to resolve inflammation, improve lymphatic function, and rescue defective tissue repair in obesity and T2D. In health, the acute inflammatory response that occurs during tissue injury is actively resolved, setting the stage for tissue repair. Pro-resolving lipid mediators, such as the resolvins, are critical mediators of active resolution of inflammation in part because they blunt inflammatory cytokine production and stimulate macrophage-mediated clearance of dead cells. We recently found that resolvins are generated in skin wounds and hasten tissue repair. Moreover, in work in progress, we discovered that specific receptors for resolvins are expressed on both macrophages and lymphatic vessels in skin wounds and that resolvin D2 (RvD2) reduces wound edema. Based on these exciting findings, we hypothesize that RvD2 engages its receptor on macrophages and lymphatic endothelial cells (LEC) to orchestrate clearance mechanisms during resolution to facilitate tissue repair. To this end, we propose to elucidate the role of RvD2 and its receptor in resolution of inflammation and edema during wound healing and determine the relative contribution of macrophages and LEC to this process by selectively deleting the RvD2 receptor in each cell type in vivo. We will uncover the mechanisms whereby RvD2 and its receptor regulate functions of macrophages and LEC important for resolution and edema clearance, and whether these processes can be rescued by RvD2 in obese-diabetic mice. Successful completion of these studies will uncover completely new roles of RvD2 and its receptor in macrophage and lymphatic function and could inform novel agonist-based approaches to rescue defective tissue repair in obesity and T2D, as well as other chronic inflammatory diseases.

项目总结/文摘