Regulation of ChemR23 in Resolution of Inflammation

ChemR23 在炎症消退中的调节

• 批准号: 9076616
• 负责人: Marcelo Freire
• 金额: $ 23.83万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076616
• 关键词: Adult; Agonist; American; Antibodies; Award; Biological; Biology; Biomimetics; CMKLR1 gene; Cells; Centers for Disease Control and Prevention (U.S.); Child; Chronic; Clinical Management; Clinical Pathology; Dental Schools; Development; Diabetes Mellitus; Diagnosis; Disease; Eicosapentaenoic Acid; Engineering; Ensure; Event; Fatty Acids; Foundations; Future; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Goals; Health; Homeostasis; Human; Inflammation; Inflammatory; Institutes; Knowledge; Lead; Learning; Ligands; Lipids; Mediating; Medicine; Mentors; Molecular; Monoclonal Antibodies; Non-Insulin-Dependent Diabetes Mellitus; Oral; Pathway interactions; Patients; Periodontal Diseases; Periodontitis; Phase; Phenotype; Prevalence; Prevention; Process; Proteomics; Regulation; Research; Resolution; Risk; Risk Factors; Role; Structure; Testing; Therapeutic antibodies; Time; Training; Training Programs; Translating; Work; attenuation; cytokine; experience; glycemic control; human CMKLR1 protein; human disease; improved; interest; macrophage; medical specialties; monocyte; neutrophil; novel therapeutics; receptor; therapeutic development

DESCRIPTION (provided by applicant): Loss of inflammation regulation is a biological event common to many human chronic inflammatory diseases including Type II diabetes mellitus, and periodontitis. A return to homeostasis (resolution of inflammation) requires cellular activation of a well-coordinated process mediated by endogenous lipids, including, resolvin E1 (RvE1), derived from the �-3 fatty acid, eicosapentaenoic acid (EPA). Activation of the G protein-coupled receptor, ChemR23, by the agonist ligand RvE1 is known to lead to attenuation of NF-KB mediated pro-inflammatory cytokines, dictating cellular fate and consequently resolution of inflammation. However, how ChemR23 in innate cells fails to activate resolution in chronic inflammatory diseases remains unclear. This proposal will test the hypothesis that ChemR23 expression and function are altered in chronic inflammatory diseases and that engineered agonist biomimetic antibodies to chemR23 can impact the inflammatory phenotype. To that end, four distinct but complementary specific aims are proposed. The mentored phase of the proposal will be carried out under Prof. Van Dyke at The Forsyth Institute. The goal of the K99 mentored phase is to: 1) characterize the expression of ChemR23 receptors on inflammatory cells (neutrophils and monocyte/macrophages) of subjects with Type II diabetes and/or periodontitis; 2) characterize the molecular pathways that are regulated by ChemR23 in disease. This training will provide expertise in inflammation biology, clinical pathology and proteomics. The understanding of ChemR23 in dictating the path chronic inflammation diseases investigated during the mentored phase will provide the foundation for transition to independent phase. Inflammation resolution is a rapidly emerging field of interest that would greatly benefit from unexplored biomimetic approaches to therapeutically regulate cell fate. Building on previous experience, the goal of R00 independent phase is to: 3) engineer agonist monoclonal antibody for ChemR23, and 4) to characterize the cellular and molecular mechanisms by which therapeutic antibodies regulate inflammation through ChemR23 activation. This award includes a well-structured training program that provides course work and seminar learning experiences as well as ensuring protected research time during concurrent specialty training in Periodontology at Harvard School of Dental Medicine. Successful completion of this project will lead to better understanding of the molecular and cellular role of ChemR23, and to translate this knowledge for the development of agonist biomimetics to modulate inflammatory diseases clinically.

描述（由申请人提供）：炎症调节的丧失是许多人类慢性炎症疾病（包括 II 型糖尿病和牙周炎）常见的生物事件。恢复稳态（炎症消退）需要细胞激活。 一个由内源性脂质介导的协调良好的过程，包括源自α-3脂肪酸二十碳五烯酸（EPA）的resolvin E1（RvE1），激动剂配体RvE1激活G蛋白偶联受体ChemR23。已知会导致 NF-KB 介导的促炎细胞因子减弱，决定细胞命运并最终消除炎症。先天细胞中的 ChemR23 未能激活慢性炎症疾病的解决尚不清楚，该提案将检验慢性炎症疾病中 ChemR23 表达和功能发生改变以及 chemR23 的工程激动剂仿生抗体可以影响炎症表型的假设。该提案的指导阶段将在福赛斯研究所的 Van Dyke 教授的领导下进行，提出了四个不同但互补的具体目标。 1) 表征 II 型糖尿病和/或牙周炎受试者炎症细胞（中性粒细胞和单核细胞/巨噬细胞）上 ChemR23 受体的表达；2) 表征疾病中受 ChemR23 调节的分子途径。生物学、临床病理学和蛋白质组学对 ChemR23 在指导阶段研究的慢性炎症疾病路径的理解将为过渡到独立阶段奠定基础。炎症消退是一个快速新兴的领域，它将极大地受益于未探索的治疗性调节细胞命运的仿生方法，R00 独立阶段的目标是：3）设计 ChemR23 的激动剂单克隆抗体，4）描述治疗性抗体通过 ChemR23 激活调节炎症的细胞和分子机制。该奖项包括一个结构良好的培训计划，提供课程作业和研讨会学习经验，并确保受保护的研究时间。在哈佛大学牙科医学院牙周病学专业培训期间，该项目的成功完成将有助于更好地了解 ChemR23 的分子和细胞作用，并将这些知识转化为激动剂仿生剂的开发，以调节临床炎症性疾病。