Intra-Articular Drug Delivery Modulating Immune Cells in Inflammatory Joint Disease

关节内药物递送调节炎症性关节疾病中的免疫细胞

基本信息

批准号：
10856753
负责人：
Nisarg J. Shah
金额：
$ 22.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10856753
关键词：
Acids Address Adjuvant Adoptive Transfer Adrenal Cortex Hormones Affect Afferent Neurons Analgesics Animal Model Anti-Inflammatory Agents Area Arthralgia Arthritis Astrocytes Attenuated Autoimmune Bolus Infusion CD4 Positive T Lymphocytes Cartilage Cells Chromatin Complex Development Disease Disease remission Disease-Modifying Second-Line Drugs Drug Delivery Systems Early treatment Evaluation Future Glial Fibrillary Acidic Protein Glycolates Goals Human Iatrogenesis Immune Immunodeficient Mouse Immunohistochemistry Infection Infiltration Inflammation Inflammatory Inflammatory Arthritis Intra-Articular Injections Joints Lead Macrophage Macrophage Activation Malignant Neoplasms Maps Measures Mechanics Mediating Microglia Modeling Modification Mus Neurons Neuropathy Nociception Pain Pain Measurement Pain management Pathogenicity Pathology Pathway interactions Patients Peripheral Nerves Phenotype Polymers Prognosis Property Proteins Proteoglycan Publishing Regulatory T-Lymphocyte Rheumatoid Arthritis Risk Role Spinal Spinal Cord Spinal Ganglia Steroids Structure Subcutaneous Injections Symptoms Systemic disease T-Lymphocyte TNF gene Testing Tissues Tretinoin Vertebral column Work activating transcription factor 3 adverse event risk allodynia arthritic pain arthropathies associated symptom autoimmune arthritis bone erosion central pain common symptom disorder control experience experimental study feasibility testing immune cell infiltrate immune modulating agents immunoreactivity immunoregulation improved in vivo inflammatory marker inflammatory pain inhibitor innovation interest mouse model nerve injury pain behavior pain inhibition pain outcome pain processing pain relief pain signal painful neuropathy parent grant particle pharmacologic standard of care transcriptomics

项目摘要

PROJECT SUMMARY Pain is a key symptom associated with joint arthropathies and can persist despite optimal control of inflammation by disease modifying anti-rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for short-term pain relief but lack disease modifying properties and their sustained use carries adverse risks. There is an unmet need for agents that can achieve durable control of pain. While the underlying mechanisms are complex, immune cells can affect the sensitization and/or activation of sensory neurons that innervate joint structures and influence pain progression. The objective of this application is to test the feasibility of leveraging immunoregulation for pain control. The project is related to the parent grant, which seeks to validate a new strategy of intra-articular (IA) drug delivery of an immunomodulatory agent that could promote disease remission in autoimmune arthritis through the enhancement of disease-protective regulatory T cells (Treg). This supplement will expand the scope of the existing aims of the parent grant and will study the T cell-pain axis in arthritis. Aim 1 will evaluate the temporal profile of pain behaviors in the SKG mouse model of T cell driven arthritis and correlate pharmacologic responsiveness to the agent with pain assessments and histopathological evaluations. Aim 2 will use SKG Treg fate mapping mice to systematically assess the role of Treg stability in pain alleviation. Aim 3 will compare pain progression in SKG mice between the Treg enhancing agent and a standard-of-care immunosuppressive DMARD. Overall, these studies will advance our goal of generating supporting evidence for T cell-focused immune mechanisms of pain and bidirectional interaction between tissue damage and pain mechanisms.

项目摘要疼痛是与关节关节病有关的关键症状，尽管最佳控制通过疾病修饰抗毒药（DMARDS）的炎症。镇痛药和皮质类固醇是通常用来补充DMARDS以缓解短期疼痛，但缺乏修饰疾病的特性及其持续使用会带来不利的风险。对代理的需求未满足，可以实现持久的控制疼痛。尽管基本机制很复杂，但免疫细胞会影响敏化和/或神经支配关节结构并影响疼痛进展的感觉神经元的激活。目的该应用是为了测试利用免疫调节以控制疼痛的可行性。该项目与父母赠款旨在验证一种新的关节内（IA）药物输送的策略免疫调节剂可以通过疾病保护调节T细胞（TREG）的增强。这种补充将扩大父母赠款的现有目的，并将研究关节炎中的T细胞辅助轴。 AIM 1将评估时间 T细胞驱动关节炎的SKG小鼠模型中疼痛行为的概况并相关药理学通过疼痛评估和组织病理学评估对药物的反应。 AIM 2将使用SKG Treg命运映射小鼠以系统地评估Treg稳定性在缓解疼痛中的作用。目标3意志比较Treg增强剂和护理标准的SKG小鼠的疼痛进展免疫抑制DMARD。总体而言，这些研究将促进我们产生支持证据的目标用于T细胞的疼痛和双向相互作用的以T细胞损伤和疼痛之间的双向相互作用机制。