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Immune modulating therapies to treat complex regional pain syndrome

免疫调节疗法治疗复杂的区域疼痛综合征

基本信息

批准号：
10583271
负责人：
Seena Ajit
金额：
$ 201.82万
依托单位：
DREXEL UNIVERSITY
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：
2022-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583271
关键词：
Acute Affect Aftercare Autoimmune Autoimmune Diseases Autoimmune Process Binding Biological Markers Biopsy Blood Blood Circulation CD4 Positive T Lymphocytes CD8B1 gene Cell surface Cells Chronic Chronic Phase Chronic disabling pain Clinical Complex Regional Pain Syndromes Coupled Data Development Disease Disease Progression Dose Etiology Flow Cytometry Fracture Functional disorder Future GTP-Binding Proteins Genes Homeostasis Hyperalgesia Hypersensitivity IL2RB gene Immune Immunotherapy Impairment Infiltration Interleukin 2 Receptor Interleukin-15 Interleukin-2 Intervention Lectin Limb structure Mediating Membrane Memory MicroRNAs Modeling Molecular Monoclonal Antibodies Mus Nerve Fibers Organ Outcome Pain Pathogenesis Pathologic Pathology Patients Peripheral Pharmacology Population Reporting Research Residencies Resolution Rodent Role STAT protein Sampling Signal Transduction Skin Sphingosine-1-Phosphate Receptor T memory cell T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Treatment outcome abuse liability allodynia antagonist autoinflammatory base cellular transduction chronic painful condition circulating microRNA cytokine cytotoxic immune function immune system function immunomodulatory therapies interleukin-15 receptor keratinocyte monocyte mouse model multiple omics novel novel therapeutic intervention receptor response response biomarker sensor sensory stimulus sex single-cell RNA sequencing stem targeted treatment tibia

项目摘要

Abstract Complex regional pain syndrome (CRPS) is a chronic pain disorder of unknown etiology that can affect one or more extremities. Difficulty in treating CRPS stems from incomplete understanding of the underlying mechanisms. Despite different clinical presentations, clear evidence for altered processing of sensory stimuli leading to allodynia, hyperalgesia, and hyperaesthesia has been demonstrated in CRPS. Aberrant immune function is reported to contribute to CRPS pathology. Autoinflammatory and autoimmune mechanisms in the skin of the affected limb, and systemically in circulation, reportedly contribute to increased pain hypersensitivity. Systemically, CRPS patients have increased proinflammatory monocytes, and altered circulating memory T cells (Tcircm). An expansion of long-lived central memory CD8+ and CD4+ T cells with increased proinflammatory signaling is reported in CRPS patients. However, current studies on Tcircm do not account for local tissue-resident memory T cells (Trm) which have been implicated in several autoimmune disorders. Cluster of differentiation 69 (CD69) is a type II C-lectin membrane receptor that is rapidly induced upon T cell activation, enabling their accumulation in nonlymphoid tissues like skin. CD69 antagonizes the cell-surface expression of G-protein– coupled sphingosine-1-phosphate receptor-1 and 5 (S1PR1/5). By inhibiting the expression of S1PR1/5, CD69 impairs egress and promotes T cell residency. We have identified dysregulation of circulating miRNA signatures common to both CRPS patients and mouse tibia fracture model (TFM) of CRPS that can regulate Tcircm. Interestingly several miRNAs, including a miRNA directly associated with positive outcomes for CRPS patients, can target genes critical to Trm development. This led us to evaluate Tcircm and Trm dysfunction in TFM mice, where preliminary data demonstrate formation of pathological Trm in TFM mice. We hypothesize that dysregulation of T cells in CRPS converges on targets crucial for both Tcircm homeostasis and Trm formation. We will test whether pathological Tcircm and Trm contribute to CRPS pathology, and if therapies that cooperatively target both populations can serve as a novel therapeutic strategy. By following Tcircm and Trm, we will elucidate mechanisms of T cell dysfunction and investigate novel immune modulating therapies for treating CRPS.

摘要