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性疾病的共同生物学事件，包括II型糖尿病和牙周炎。回归动态平衡(消退炎症)需要细胞激活 由内源性脂类介导的一种协调良好的过程，包括从�-3脂肪酸二十碳五烯酸(EPA)中衍生出来的解决素E1(Rve1)。已知的是，激动剂配体RvE1激活G蛋白偶联受体ChemR23会导致核因子-KB介导的促炎细胞因子的减弱，从而决定细胞的命运，从而决定炎症的消退。然而，天然细胞中的ChemR23如何未能激活慢性炎症性疾病的分解仍不清楚。这项提议将检验以下假设：在慢性炎症性疾病中，ChemR23的表达和功能发生了变化，并且针对ChemR23的工程激动剂仿生抗体可以影响炎症表型。为此，提出了四个截然不同但相辅相成的具体目标。该提案的指导阶段将在福赛斯研究所的范·戴克教授的指导下进行。K99指导阶段的目标是：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/巨噬细胞)上ChemR23受体的表达；2)表征在疾病中由ChemR23调控的分子通路。这项培训将提供炎症生物学、临床病理学和蛋白质组学方面的专业知识。了解ChemR23在指导阶段所研究的慢性炎症性疾病的路径将为过渡到独立阶段提供基础。炎症消退是一个迅速兴起的兴趣领域，它将极大地受益于尚未探索的从治疗上调节细胞命运的仿生方法。在以往经验的基础上，R00独立期的目标是：3)为ChemR23设计激动型单抗，以及4)表征治疗性抗体通过激活ChemR23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，该计划提供课程工作和研讨会学习经验，并确保在哈佛大学牙医学院牙周学专业培训期间保护研究时间。该项目的成功完成将有助于更好地理解ChemR23的分子和细胞作用，并将这些知识转化为开发激动剂仿生药物，以调节临床上的炎症性疾病。