RF1NS130481

Title: Immune Modulating Therapies to Treat Complex Regional Pain Syndrome

Abstract:

Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder that affects one or more extremities. The difficulty in treating CRPS stems from an incomplete understanding of the underlying mechanisms. Despite different clinical presentations, clear evidence for altered processing of sensory stimuli leading to allodynia, hyperalgesia, and hyperesthesia has been demonstrated in CRPS. Aberrant immune function is reported to contribute to CRPS pathology, with autoinflammatory and autoimmune mechanisms in the skin of the affected limb and systemically in circulation reportedly contributing 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.

The researchers have identified dysregulation of circulating miRNA signatures common to both CRPS patients and a mouse tibia fracture model (TFM) of CRPS that can regulate TCIRCM. Interestingly, several miRNAs, including one directly associated with positive outcomes for CRPS patients, can target genes critical to TRM development. This led them to evaluate TCIRCM and TRM dysfunction in TFM mice, where preliminary data demonstrate the formation of pathological TRM.

The hypothesis is that dysregulation of T cells in CRPS converges on targets crucial for both TCIRCM homeostasis and TRM formation. The researchers 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, they aim to elucidate mechanisms of T cell dysfunction and investigate novel immune modulating therapies for treating CRPS.

Drexel University

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Philadelphia, Pennsylvania 19102 United States

Single Zip Code

HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) (RFA-NS-22-034)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 63% from $2,018,200 to $3,283,186.