Regulation of ChemR23 in Resolution of Inflammation

ChemR23 在炎症消退中的调节

• 批准号: 9750754
• 负责人: Marcelo Freire
• 金额: $ 24.32万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-09 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750754
• 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; Clinical Management; Clinical Pathology; Dental Schools; Development; Diabetes Mellitus; Diagnosis; Disease; Eicosapentaenoic Acid; Engineering; Ensure; Event; Fatty Acids; Foundations; Future; G-Protein-Coupled Receptors; Goals; Homeostasis; Human; Inflammation; Inflammatory; Institutes; Knowledge; LTB4R gene; Lead; Learning; Ligands; Lipids; Mediating; Medicine; Mentors; Molecular; Monoclonal Antibodies; NF-kappa B; 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; Therapeutic antibodies; Time; Training; Training Programs; Translating; Work; attenuation; cytokine; experience; glycemic control; human disease; improved; interest; macrophage; medical specialties; monocyte; neutrophil; novel therapeutics; public health relevance; 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（通过应用提供）：炎症调节的丧失是许多人类慢性炎症性疾病（包括II型糖尿病和牙周炎）常见的生物学事件。回到体内平衡（炎症的分辨率）需要细胞激活 由内源性脂质介导的良好协调过程，包括溶质E1（RVE1），源自eicosapentaenoic Acid（EPA）。已知激动剂配体RVE1的G蛋白偶联受体ChemR23的激活导致NF-KB介导的促炎细胞因子的衰减，这决定了细胞命运，并因此解决了炎症。然而，先天细胞中的ChemR23无法激活慢性炎症性疾病的分辨率尚不清楚。该提案将检验以下假设：慢性炎症性疾病中ChemR23的表达和功能会改变，并且对ChemR23进行工程的激动剂仿生抗体会影响炎症表型。为此，提出了四个不同但互补的特定目标。该提案的指导阶段将在福赛斯研究所的范·戴克（Van Dyke）教授的领导下进行。 K99修补阶段的目的是：1）表征具有II型糖尿病和/或牙周炎的受试者对炎性细胞（中性粒细胞和单核细胞/巨噬细胞）上炎性细胞（中性粒细胞和单核细胞/巨噬细胞）的表达； 2）表征疾病中由ChemR23调节的分子途径。该培训将在炎症生物学，临床病理学和蛋白质组学方面提供专业知识。在指示修补阶段研究的慢性炎症疾病时，对ChemR23的理解将为过渡到独立阶段提供基础。炎症分辨率是一个快速新兴的感兴趣领域，它将从治疗调节细胞脂肪的意外仿生方法中受益匪浅。基于先前的经验，R00独立阶段的目标是：3）ChemR23的工程师激动剂单克隆抗体，以及4）表征细胞和分子机制，通过该机制，治疗抗体通过ChemR23激活来调节炎症。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半学习经验，并确保在哈佛大学牙科医学学院的牙周病学特殊培训期间受到保护的研究时间。该项目的成功完成将使人们更好地了解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剂以在临床上调节炎症性疾病。

项目成果

Oral Microbial Species and Virulence Factors Associated with Oral Squamous Cell Carcinoma.

• DOI: 10.1007/s00248-020-01596-5
• 发表时间: 2021-11
• 期刊: Microbial ecology
• 影响因子: 3.6
• 作者: Torralba MG;Aleti G;Li W;Moncera KJ;Lin YH;Yu Y;Masternak MM;Golusinski W;Golusinski P;Lamperska K;Edlund A;Freire M;Nelson KE
• 通讯作者: Nelson KE