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Osteomucosal healing and immunity in medication-related osteonecrosis of the jaw

药物相关颌骨坏死的骨粘膜愈合和免疫

基本信息

批准号：
10870267
负责人：
Yousang Gwack
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-19 至 2024-07-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10870267
关键词：
Animal Model Area Automobile Driving Bone necrosis Cell Differentiation process Cell Lineage Cells Chronic Clinical Data Dental Pulp Development Disease Dose Event Exposure to Foundations Functional disorder Future Genetic Gingiva Goals Health IL17 gene Iatrogenesis Immune Immunity Immunotherapy Infiltration Inflammation Inflammatory Injections Interleukin-6 Intervention Jaw Knockout Mice Lesion Ligature Link Lipopolysaccharides Malignant Neoplasms Maps Metastatic Neoplasm to the Bone Modality Molecular Mouth Diseases Mus Myelogenous Necrosis Osteoporosis Osteoporosis prevention Pathogenesis Pathogenicity Pathologic Periapical Periodontitis Periodontitis Pharmaceutical Preparations Pre-Clinical Model Public Health Publishing Quality of life Regulatory T-Lymphocyte Reporting Role Severities Signal Pathway Source Submucosa Testing Therapeutic Tissues Tooth Extraction attenuation bisphosphonate bone cytokine debilitating pain healing in vivo insight interleukin-23 mouse model neutralizing antibody oral bacteria palliative pharmacologic receptor response soft tissue therapeutically effective

项目摘要

ABSTRACT Medication-related osteonecrosis of the jaw (MRONJ) is a destructive, non-healing intraoral lesion that preferentially occurs after long-term use of anti-resorptive medications (ARMs) such as bisphosphonates (BPs) or denosumab (Dmab) used for treating osteoporosis or bone malignancy. MRONJ severely diminishes quality of life, often causes debilitating pain, and imposes other significant health issues. Because so little is known about MRONJ pathophysiology and current treatments are largely palliative, there is an urgent need to better understand the underlying pathogenetic mechanisms and develop effective therapeutic modalities. During the past decade, our interdisciplinary team has developed various MRONJ mouse models, results of which point to dysregulation of osteomucosal immunity as the leading source of MRONJ pathophysiology. Our long-term goal is to understand the basis of osteomucosal immunity in MRONJ pathophysiology and evaluate the use of targeted immunotherapies to mitigate MRONJ prior to its clinical presentation. Guided by our previously published studies as well as unpublished preliminary data, we hypothesize that MRONJ pathogenesis is associated with altered osteomucosal immunity and immune cell plasticity via pathologic amplification of the IL- 36/IL-23/Th17 axis in the presence of inflammatory oral diseases and ARMs. The objectives of this proposal are: 1) to define how IL-36 functions as an initiator MRONJ pathogenesis; 2) to delineate the bridging role of IL-23 from IL-36 to augmenting Th17 pathogenicity in MRONJ; and 3) to determine the pathologic role of Th17 cells during MRONJ progression. Completion of our proposed studies will provide the foundational framework to harness MRONJ via immunotherapy and interventions for future clinical uses.

摘要