Funded Projects

Oral cancers are painful and often require use of opioid medications to manage pain. However, the effectiveness of opioids often wanes quickly, and many patients require higher doses because they develop tolerance to these medications. This project will study the potential value of blocking epidermal growth-factor receptors interacting with peripheral nerves to treat oral cancer pain. The findings will advance understanding of the molecular mechanisms underlying oral cancer pain and provide a rationale for repurposing epidermal growth-factor receptor blockers, which is already approved for head and neck cancer treatment for treating oral cancer and associated pain.

Human oral cancer is associated with significant chronic pain, and a comprehensive understanding of the biology and mechanisms underlying this chronic pain is critical for developing better pain management strategies. This project will determine molecular characteristics, including a specific signaling system (endosomal GPCR kinase), associated with chronic oral cancer pain, using tissue samples obtained from patients with this condition. The findings will then be used to inform studies in animal models of human oral cancer pain to enhance understanding how endosomal GPCR kinase contributes to human oral cancer pain.

Neuropathic pain is a debilitating affliction present in 26% of diabetic patients, with substantial impact on the quality of life. Despite this significant impact and prevalence, current therapies for painful diabetic neuropathy (PDN) are only partially effective, and the molecular mechanisms underlying neuropathic pain in diabetes are not well understood. Our long-term goal is to elucidate the molecular mechanisms responsible for PDN in order to provide targets for the development of therapeutic agents. Our objective is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration. Our aims will determine: 1) the ion-channel current profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; 2) the gene expression profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; and 3) the specific features of nociceptor mitochondrial dysfunction produced by CXCR4/SDF-1 signaling in PDN.

Neuropathic pain is a debilitating and complex medical condition for which safe and non-addictive treatment options are urgently needed. This project aims to develop new strategies for treating neuropathic pain by controlling the activity of transmembrane protein 97 (TMEM97), also known as the sigma 2 receptor, which has been shown to relieve pain in an animal model of neuropathic pain. The research aims to develop a new molecule that increases TMEM97 activity and is safe for human use, toward obtaining approval from the U.S. Food and Drug Administration for Phase I clinical testing. 

Identification of new targets and mechanisms underlying chronic neuropathic pain is essential for the discovery of novel treatments and preventative tactics for better neuropathic pain management. A recent exploration of next-generation RNA sequencing identified a large, native, full-length long noncoding RNA (lncRNA) in mouse and human dorsal root ganglion (DRG). It was named as nerve injury-specific lncRNA (NIS-lncRNA), since its expression was found increased in injured DRGs, in response to peripheral nerve injury, but not in response to inflammation. Preliminary findings revealed that blocking the nerve injury-induced increases in DRG NIS-lncRNA levels ameliorated neuropathic pain. This project will validate NIS-lncRNA as a therapeutic target in animal models of neuropathic pain and in cell-based functional assays utilizing human DRG neurons. Completion of this proposal will advance neuropathic pain management and might provide a novel, non-opioid pain therapeutic target.

Neuropathic pain is a debilitating and complex medical condition for which safe and non-addictive treatment options are urgently needed. Preliminary studies have found that lysophosphatidic acid receptor 5 (LPA5) is present in areas of the body that signal pain, including at high levels in rodent models of neuropathic pain. This project will use genetic and pharmacological approaches to determine whether blocking LPA5 signaling reduces neuropathic pain toward future testing in humans.  

This project will use a variety of technologies to create a comprehensive, 3D map of how sensory neurons activate knee joints in both mice and humans. The research will use imaging techniques and molecular approaches that measure gene expression. The findings will help create a comprehensive gene expression profile map of individual cells in the nerve fibers leading to the knee, as well as describe how nerve cells and joint cells interact at the most fundamental level. This research will generate a rich anatomical and molecular resource to understand the molecular basis of joint pain and guide the development of novel pain-relieving strategies.

Neuropathic pain conditions are difficult to treat, and novel non-narcotic analgesics are desperately needed. The G protein-coupled receptor 160 (GPR160) has emerged as a novel target for analgesic development, as GPR160 in the spinal cord may play a role in the transition from acute to chronic pain. Cocaine- and Amphetamine-Regulated transcript peptide (CARTp) was identified as a ligand for GPR160. Blocking endogenous CARTp signaling in the spinal cord attenuates neuropathic pain, whereas intrathecal injection of CARTp evokes painful hypersensitivity in rodents through GPR160-dependent extracellular signal-regulated kinase (ERK) and cyclic AMP response element-binding pathways (CREB). This project will isolate and biochemically characterize GPR160 and establish methods for biochemical characterization of GPR160 interaction with CARTp activator. Researchers will miniaturize and optimize biochemical assay and scale up protein production for future high throughput biochemical screening to identify potent inhibitors of GPR160 activation. These studies are critical for defining the molecular mechanism of CARTp/GPR160 interactions and initiating large-scale screens for new inhibitors to develop novel therapeutics.

We propose to develop a safe and effective nonopioid analgesic to treat neuropathic pain that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Development of systemic NaV1.7 inhibitors has been complicated by the challenge of achieving selectivity over other NaV isoforms expressed throughout the body. We have discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.

Neuropathic pain conditions are exceedingly difficult to treat, and novel non-opioid analgesics are desperately needed. Receptomic and unbiased transcriptomic approaches recently identified the orphan G-protein coupled receptor (oGPCR), GPR160, as a major oGPCR whose transcript is significantly increased in the dorsal horn of the spinal cord (DH-SC) ipsilateral to nerve injury, in a model of traumatic nerve-injury induced neuropathic pain caused by constriction of the sciatic nerve in rats (CCI). De-orphanization of GPR160 led to the identification of cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand which activates pathways crucial to persistent pain sensitization. This project will test the hypothesis that CARTp/GPR160 signaling in the spinal cord is essential for the development and maintenance of neuropathic pain states. It will also validate GPR160 as a non-opioid receptor target for therapeutic intervention in neuropathic pain, and characterize GPR160 coupling and downstream molecular signaling pathways underlying chronic neuropathic pain.

The research team has developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. This project will clinically translate ultrasonic ketamine uncaging for chronic pain therapy. In the UG3 phase, the research team will scale our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. In the UH3 phase, they will complete a first-in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. This project aims to yield a novel, noninvasive, non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

Multidisciplinary chronic pain treatments show incomplete recovery at the population level because of significant heterogeneity on the individual level in the high impact chronic pain population. Subgroups of individuals either completely respond, do not change, or even worsen following pain management. Therefore, diagnostic biomarker signatures are needed to differentiate high impact chronic pain from low impact chronic pain. This study aims to develop prognostic biomarkers to predict the disease trajectory for individuals with musculoskeletal high-impact chronic pain. These biomarker signatures will integrate central nervous system (CNS), multi-?omic?, sensory, functional, psychosocial, and demographic domains into detection algorithms. Biomarker signatures from the proposed research are intended to facilitate risk and treatment stratification for clinical trial design and to facilitate treatment decisions in clinical practice for patients with musculoskeletal chronic pain.

Technology approaches that deliver electrical current through the skin near a damaged or injured peripheral nerve are used to treat chronic neuropathic pain that does not respond to other treatments. This project will optimize this nerve stimulation approach while also determining how the stimulation works to reduce pain in the body. The research will also look for patient characteristics that predict response by conducting a clinical trial comparing combined peripheral nerve stimulation and conventional medical treatment to medication alone.