POP2 as a novel therapeutic in rheumatoid arthritis

POP2 作为类风湿关节炎的新型治疗方法

基本信息

批准号：
10709887
负责人：
JONATHAN A HARTON
金额：
$ 17.93万
依托单位：
ALBANY MEDICAL COLLEGE
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：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709887
关键词：
Affect American Anti-Inflammatory Agents Antiinflammatory Effect Arthritis Atherosclerosis Autoimmune Diseases Autoimmunity Biochemical Biological Response Modifier Therapy Cartilage Cell Culture Techniques Cells Characteristics Chromosome 3 Chronic Clinical Code Collagen Arthritis Data Disease Dose Event Genes Human IL18 gene Immunity Immunologics In Vitro Incidence Individual Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interleukin-1 beta Interleukin-6 Investigation Joints Knowledge Laboratory Animals Longevity Macrophage Measures Mediating Metabolic Diseases Modeling Molecular Mus NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Outcome Pathology Pathway interactions Patients Penetration Peptides Pre-Clinical Model Primates Production Property Proteins Publishing Quality of life Recombinants Regimen Reporting Rheumatoid Arthritis Route Severities Signal Transduction Source Stimulus Synovial Membrane System TNF gene Tertiary Protein Structure Therapeutic Therapeutic Uses Transgenic Mice Treatment Protocols United States bone erosion comorbidity constitutive expression cytokine empowerment experience improved in vivo inducible gene expression infection risk insight joint injury loss of function marenostrin mouse model novel novel therapeutic intervention novel therapeutics overexpression pre-clinical preclinical study restraint stem targeted treatment transcription factor

项目摘要

Project Summary: Inflammation underlies the disabling manifestations and co-morbidities of rheumatoid arthritis (RA). Treatment regimens for RA patients aim to control inflammation and progressive joint damage mediated by inflammatory cytokines including TNFα, IL-1β, and IL-6. Recent studies demonstrate that humans possess four genes coding Pyrin-only proteins (POPs) that limit NF-B signaling and inflammasome activation pathways, events critical for elaboration of the cytokines mediating inflammation. TNF, IL-1β, and IL-6 are critically regulated by NF-B transcription factors. We have previously described the anti-inflammatory properties of POP2 in-vitro and in-vivo. Here we propose proof-of-concept studies to evaluate how POP2 and POP2-derived peptides impact experimentally induced RA when administered exogenously, using a murine preclinical model. POP2 peptide therapy represents a novel therapeutic approach to ameliorating excessive inflammation through dual inhibition of both NF-B signaling and inflammasome pathways. The immunological and molecular basis for our hypotheses stems from our published and preliminary data showing the naturally expressed, non-toxic POP2 peptide dampens cytokine production in inflammatory responses without compromising host immunity. Our studies will provide insight into how treatment regimens based on POP2 peptide therapy may be utilized or improved upon. In vitro characterization, dose-escalation studies and in-vivo assessment of disease parameters will inform approaches to develop POP2 peptides as a novel therapeutic.

项目摘要：炎症是类风湿关节炎（RA）的残疾表现和合并症的基础。治疗 RA患者的方案旨在控制炎症介导的炎症和进行性关节损伤包括TNFα，IL-1β和IL-6在内的细胞因子。最近的研究表明，人类拥有四个基因限制NF-B信号传导和炎症体激活途径的仅编码吡啶蛋白（POPS），事件对介导炎症的细胞因子阐述至关重要。 TNF，IL-1β和IL-6受到严格调节 NF-B转录因子。我们先前已经描述了POP2 In-Vitro的抗炎特性和体内。在这里，我们提出了概念验证研究，以评估POP2和POP2衍生的肽使用鼠临床前模型，当外源施用外源性时，撞击实验诱导的RA。 POP2 肽疗法代表了一种新型的热方法，可通过双重改善多余的炎症抑制NF-B信号传导和炎性途径。免疫学和分子基础我们的假设从我们发表的初步数据中显示出植物，显示自然表达的无毒 POP2辣椒在没有损害宿主免疫力的炎症反应中的细胞因子产生。我们的研究将提供有关如何利用基于POP2胡椒疗法的治疗方案或改进。体外表征，剂量升级研究和体内疾病评估参数将为开发Pop2 Pepperides的方法提供信息，作为一种新的疗法。