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A novel role for Reelin therapeutics in rheumatoid arthritis

Reelin 疗法在类风湿性关节炎中的新作用

基本信息

批准号：
10545705
负责人：
Maria Z Kounnas
金额：
$ 30万
依托单位：
REELIN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545705
关键词：
Adhesions Affect Affinity American Anti-Inflammatory Agents Antibodies Ants Apolipoproteins Area Arthritis Attenuated Autoimmune Diseases Binding Biological Models Blood Vessels Cartilage Cell Adhesion Molecules Cells Chronic Clinical DNA Sequence Alteration Data Degenerative Disorder Disease Disease Progression Disease remission E-Selectin Endothelial Cells Endothelium Etiology Event Extracellular Matrix Proteins Extravasation Glucocorticoids Human Immunologic Receptors In Vitro Individual Infiltration Inflammation Inflammatory Intercellular adhesion molecule 1 Intervention Lead Leukocyte Adhesion Molecules Leukocytes Methods Methotrexate Modification Molecular Monitor Monoclonal Antibodies Pathology Pathway interactions Patients Pharmaceutical Preparations Plasma Plasma Proteins Process Property Proteins Quality of life Receptor Cell Rheumatoid Arthritis Role Site Source Swelling Symptoms Synovial Fluid Synovial Membrane Synovial joint Synovitis System Testing Therapeutic Tissues Vascular Cell Adhesion Molecule-1 Vascular Endothelium apolipoprotein E receptor 2 base bone cytokine disability experience human model inflammatory milieu joint destruction kinase inhibitor leukocyte proliferation mouse model novel receptor recruit screening targeted agent tissue degeneration treatment strategy tumor necrosis factor-alpha inhibitor

项目摘要

Abstract Chronic inflammatory pathology of cartilage and bone represents a major source of damage to the synovial joints observed in rheumatoid arthritis (RA). Although the precise etiology of these diseases is often unknown, excessive leukocyte extravasation is a substantial contributor to the tissue damage/inflammation and our recent data show a prominent role of the plasma protein, Reelin in this process. Furthermore, we have now shown that it is possible, using anti-Reelin monoclonal antibodies, to deplete the plasma of Reelin, which results in a significant reduction of a wide range of vascular adhesion molecule expression. Thus, in contrast to the current methods of depleting individual adhesion molecules or immune receptors, our anti-Reelin approach systematically downregulates all major inflammation-driven adhesion proteins on the vascular endothelium. The purpose of this proposal is to demonstrate the role of Reelin in RA by 1) identifying high affinity Reelin antibodies and 2) validating the therapeutic potential of mitigating chronic inflammatory milieu with an anti-Reelin antibody in an RA mouse model.

摘要软骨和骨的慢性炎性病理学代表了骨损伤的主要来源，类风湿性关节炎（RA）中观察到的滑膜关节。虽然这些疾病的确切病因疾病通常是未知的，过度的白细胞外渗是导致疾病的重要因素。组织损伤/炎症和我们最近的数据显示血浆蛋白的突出作用，在这一过程中，此外，我们现在已经证明，使用反Reelin 单克隆抗体，以消耗血浆中的Reelin，这导致显著减少广泛的血管粘附分子表达。因此，与当前相比，消耗单个粘附分子或免疫受体的方法，我们的抗Reelin 这种方法系统地下调了所有主要的炎症驱动的粘附蛋白，血管内皮本提案的目的是证明Reelin在RA中的作用通过1）鉴定高亲和力Reelin抗体和2）验证在RA小鼠模型中用抗Reelin抗体减轻慢性炎症环境。