Funded Projects

There is increasing evidence that satellite glial cells (SGCs) surrounding neurons in the dorsal root ganglia modulate sensory processing and are important for chronic pain. Tissue inhibitor of metalloproteinase 3 (TIMP3) signaling occurs in SGCs and has unique plethoric functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-?-converting enzyme, and the vascular endothelial growth factor receptor 2, all of which have been implicated in inflammation and pain. This study will test the hypothesis that expression of TIMP3 in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as for the development of pain, and therefore could be a novel therapeutic target for acute and chronic pain. Given the expression of TIMP3 in human SGCs and the strong validation of multiple small molecules targeting TIMP3 signaling, including FDA-approved drugs, in various animal models of pain and in cultured human SGCs, the successful completion of this research project has a high likelihood of rapid translation into therapeutic testing in inflammatory pain conditions that are a risk for opioid abuse.

Taxanes are among the most effective chemotherapeutic agents and are frequently used in the treatment of early stage and metastatic breast cancer. However, they are known to produce a pain condition known as Chemotherapy-Induced Peripheral Neuropathic Pain (CIPNP). CIPNP is one of the primary reasons a patient receives a limited dose of taxane. No diagnostic tool exists to identify patients that will develop CIPNP in response to taxane therapy. Biomarker signatures associated with taxane-induced neuropathic pain will be developed to: 1) identify patients at risk for developing debilitating taxane neuropathic pain before chemotherapy is initiated; and 2) to identify patients already on treatment who are at risk of developing neuropathic pain and need dosing adjustments to prevent CIPNP symptoms. This biomarker signature will be used to detect CIPNP-susceptible patients early and personalize their taxane therapy to minimize CIPNP while optimizing the therapeutic taxane dosing.

African American adults are less likely to receive analgesics, particularly opioids. Research in the pediatric surgical population is limited, but the pattern of disparate use of opioids appears consistent with adults. Furthermore, adolescent access to prescribed opioids has increased, both through physician prescribing and misuse of medications prescribed to family members or friends. This study will explore the interrelated impacts of policy, clinical need, and sociodemographic factors by combining Medicaid claims and electronic health record data with findings from a statewide opioid policy inventory. We will focus on discharge prescribing of opioids in three high-volume pediatric surgical procedures: tonsillectomy/adenoidectomy, supracondylar fracture, and appendectomy. We aim to 1) determine the extent of racial disparities in postoperative discharge opioid prescribing since the 2011 onset of enhanced opioid prescription reduction activities and 2) develop an expanded model to assess the linkage between differential opioid use for pediatric postoperative pain and opioid use-related outcomes.

Efforts to identify non-opioid analgesics for treatment of chronic pain have identified a protein, carbonic anhydrase-8 (CA8), in pain-sensing nerve cells in the spinal cord (dorsal root ganglion cells) whose expression regulates analgesic responses. Gene therapy delivering CA8 to dorsal root ganglion cells through clinically relevant routes of administration functions as a “local anesthetic” that induces long-lasting pain relief in animal models of chronic pain. This project will further develop CA8 gene therapy with the goal of treating chronic knee osteoarthritis pain. It will assess several gene therapy constructs to determine the doses needed, safety, efficacy, and specificity to nerve cells for each construct. It will then select the safest and most effective construct that can be administered via the least invasive route for further development. The project will include all steps necessary to identify one candidate gene therapy construct that will be suitable to begin clinical trials in patients with chronic knee osteoarthritis pain.

Researchers will develop an innovative three-dimensional (3D) model of acute and chronic nociception using human induced pluripotent stem cell (hiPSC) sensory neurons and satellite glial cell surrogates. They will develop a tissue chip for modeling acute and chronic nociception based on 3D hiPSC-based dorsal root ganglion tissue mimics and a high-content, moderate-throughput microelectrode array. Researchers will demonstrate stable spontaneous and noxious stimulus-evoked behavior in response to thermal, chemical, and electrical stimulation challenges. They aim to demonstrate sensitivity to translational control via ligand receptor interactions between neuronal and non-neuronal cell types. They also will demonstrate the quantitative efficiency and preclinical efficacy of our system by detecting known ligand-based modulators of translational control and voltage-gated ion channel antagonists in a sensitized model of chronic nociception. Researchers will leverage the high-throughput nature of our tissue chip model to screen Food and Drug Administration–approved bioactive compounds.

 Investigating the broader efficacy of sEH inhibition and specifically our IND candidate, EC5026, has indicated that it is efficacious against chemotherapy induced peripheral neuropathy (CIPN). This painful neuropathy develops from chemotherapy treatment, is notoriously difficult to treat, and can lead to discontinuation of life-prolonging cancer treatments. Thus, new therapeutic approaches are urgently needed. The research team will investigate if EC5026 has potential drug-drug interaction with approved chemotherapeutics or alters immune cells function, and assess the effects of sEHI on the lipid metabolome and probe for changes in endoplasmic reticulum stress and axonal outgrowth in neurons. The team proposes to more fully characterize the analgesic potential of our compound and investigate on and off target actions in CIPN models and model systems relevant to cancer therapy.

Pain signals originate predominantly in a subset of peripheral sensory neurons that harbor a distinct subset of voltage-gated sodium (NaV) channels; however, current NaV channel blockers, such as local anesthetics, are non-selective and also block NaV channels vital for function of the heart, muscle, and central nervous system. Genetic studies have identified human NaV1.7, NaV1.8, and NaV1.9 channel subtypes as key players in pain signaling and as major contributors to action potential generation in peripheral neurons. ProTx-II is a highly potent and moderately selective peptide toxin that inhibits human NaV1.7 activation. This study will optimize ProTx-II selectivity, potency, and stability by exploiting the new structures of ProTx-II—human NaV1.7 channel complexes, advances in rational peptide optimization, and rigorous potency and efficacy screens to generate high-affinity, selective inhibitors of human NaV1.7, NaV1.8, and NaV1.9 channels that can define a new class of biologics to treat pain.

Masticatory and spontaneous pain associated with temporomandibular joint disorders (TMJD) is a significant contributor to orofacial pain, and current treatments for TMJD pain are unsatisfactory. Pain-related transient receptor potential (TRP) channels, expressed by trigeminal ganglion (TG) sensory neurons, have been implicated in both acute and chronic pain and represent possible targets for anti-pain strategies. Using bite force metrics, we found TMJ inflammation-induced masticatory pain to be significantly, but not fully, reversed in Trpv4 knockout mice, suggesting the residual pain might be mediated by other pain-TRPs. Our gene expression studies demonstrated that TRPV1 and TRPA1 were up-regulated in the TG in response to TMJ inflammation in a Trpv4-dependent manner. We hypothesize that TRPV1 and TRPA1, like TRPV4, contribute to TMJ pain. Our specific aims will examine the contribution of TRPV1, TRPV4, and TRPA1 to pathogenesis of TMJD pathologic pain including assessment of the role of neurogenic inflammation.

Over-the-counter medicines such as non-steroidal anti-inflammatory drugs are ineffective for treating severe chronic pain and may have serious side effects from continued use, which limits treatment options. A kinase (an enzyme whose activity targets a specific molecule) called TAK1 is involved in the chronic pain process. This research will develop a molecule previously shown to be effective in a model of inflammatory pain that also inhibits TAK1. A main goal will be to determine if this inhibitor (takinib analog HS-276) can cross the blood-brain barrier and, if successful, pursue FDA  Investigative New Drug-enabling safety studies leading to a Phase I clinical trial and a potential new chronic pain treatment.

Temporomandibular joint (TMJ) disorders are the most common form of chronic pain in the face and mouth area (orofacial pain), but relatively little is known about the biological causes of these conditions. This project will define the properties of sensory neurons that connect to tissues that make up the TMJ which connects the lower jaw and skull. This research aims to lay groundwork for development of new therapeutic approaches to treat these painful conditions.

Improved pain management and reduction of opioid use could greatly benefit from improved pragmatic clinical trials (PCTs). The PRISM Resource Coordinating Center (CC), as part of the NIH Health Care Systems Research Collaboratory, will support up to nine more embedded PCTs that address pain management and the opioid crisis. Since 2012, the CC has nurtured 15 Demonstration Projects by providing leadership, resources, tools, training, and coordination of diverse elements. The CC will work collaboratively with each PRISM Demonstration Project team supported through the HEAL Initiative, including their partnering health care systems, to develop, test, and implement the projects while providing technical, design, and coordination support. The CC will also develop and refine technical and policy guidelines and best practices for the effective conduct of pain-related research studies in partnership with health care systems and disseminate best strategies for successful embedded PCTs.

A main goal of the NIH HEAL Initiative and the Early Phase Pain Intervention Clinical Network (EPPIC-Net) is to improve non-opioid pain management. This award will leverage the resources at one of EPPIC-Net’s Specialized Clinical Centers by implementing and evaluating strategies to improve the engagement, recruitment, and retention of individuals from underserved racial/ethnic minority populations to participate in EPPIC-Net clinical trials. Since environmental, cultural, and genetic factors may account for observed differences in pain responses between racial and ethnic groups, enrollment of a diverse sample in pain research is crucial to obtain a complete understanding of the effectiveness of any proposed pain therapeutic intervention. The success of these activities will be evaluated, and a toolkit will be created to define best practices that can be by other EPPIC-Net sites and additional trials.