Funded Projects

Neuropathic pain is characterized by neuronal hyperexcitability and spontaneous activity, properties associated with activity of hyperpolarization-activated, cyclic nucleotide-regulated (HCN1-4) channels, the source of the pacemaker current, Ih. Inhibition of HCN1-mediated Ih elicits marked antihyperalgesia in multiple animal models of neuropathic pain, including models for direct nerve injury and chemotherapy-induced peripheral neuropathy, and does so with little or no disruption to either normal pain processing or baseline behaviors and activities. The overall objective is to develop a peripherally restricted HCN1 inverse-agonist as a therapeutic for neuropathic pain. Researchers have generated a novel small molecule that combines an antihyperalgesic HCN1 inhibitor with a motif that controls distribution and membrane presentation and is a potential non-opioid antihyperalgesic treatment for peripheral neuropathic pain.

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in all primary afferent neurons (PANs) in trigeminal ganglion (TG) and dorsal root ganglion (DRG), mediating background K+ currents and controlling the excitability of PANs. TRESK mutations cause migraine headache but not body pain in humans, suggesting that TG neurons are more vulnerable to TRESK dysfunctions. TRESK knock out (KO) mice exhibit more robust behavioral responses than wild-type controls in mouse models of trigeminal pain, especially headache. We will investigate the mechanisms through which TRESK dysfunction differentially affects TG and DRG neurons. Based on our preliminary finding that changes of endogenous TRESK activity correlate with changes of the excitability of TG neurons during estrous cycles in female mice, we will examine whether estrogen increases migraine susceptibility in women through inhibition of TRESK activity in TG neurons. We will test the hypothesis that frequent migraine attacks reduce TG TRESK currents.

Chronic post-traumatic headache (PTH) is highly debilitating, poorly understood, and difficult to treat. This project aims to identify proteins located in the membrane of certain neurons that are critical for the development, maintenance, and/or resolution of PTH. These proteins may be targets for novel treatment approaches that are nonaddictive and have minimal side effects.

There is a continued need to discover and validate new targets for potential therapeutic strategies for effective and safe treatment of pain. This project focuses on the protein metadherin, also known as astrocyte elevated gene-1 protein (AEG-1), as a possible new target for pain treatment. Preliminary studies have shown that mice genetically engineered to lack metadherin had significantly lower inflammation and chronic pain-related behaviors. This project aims to further validate AEG-1 as a pain target and test whether reducing levels in white blood cells called macrophages might work as a therapeutic strategy to reduce chronic inflammatory and/or neuropathic pain using an innovative nanoparticle approach to target specific cells.

Effective development of non-addictive therapies for pain requires animal models that reflect the human condition. Unfortunately, currently used models have limitations and have not always done a good job of predicting what will work in human patients. This project will refine a new way of measuring pain-related behaviors in mice that takes advantage of more natural mouse behavior and is less influenced by experimenter biases and artifacts. The research will verify that the promising results hold up in several different types of pain and that different classes of clinically used pain medications are effective. They will also make sure the data can be reproduced by an outside laboratory. If successful, this will support the use of this new read-out for future pain therapy development.

Genomic medicine offers hope for improved diagnostic methods and for more effective, patient-specific therapies. Genome-wide associated studies (GWAS) elucidate genetic markers that improve clinical understanding of risks and mechanisms for many diseases and conditions and that may ultimately guide diagnosis and therapy on a patient-specific basis. Previous phenome-wide association studies (PheWAS) established a systematic and efficient approach to identifying novel disease-variant associations and discovering pleiotropy using electronic health records (EHRs). This proposal will develop novel methods to identify associations based on patterns of phenotypes using a phenotype risk score (PheRS) methodology to systematically search for the influence of Mendelian disease variants on common disease. By doing so, it also creates a way to assess pathogenicity for rare variants and will identify patients at highest risk of having undiagnosed Mendelian disease. The project is enabled by large DNA biobanks coupled to de-identified copies of EHR.

An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. Researchers have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, researchers anticipate that their compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions.

While traditional epidural spinal cord stimulation (SCS) for intractable pain has been very efficacious for the patients responsive to it, the success rate has held at approximately 55%. Dorsal root ganglion (DRG) stimulation has shown promise in early trials to provide greater pain relief. Although the decrease in back pain at 3 months was significantly greater in the DRG arm vs. SCS, the adverse event rate related to the device or implant procedure was significantly higher in the DRG arm. Researchers will develop the “Injectrode” system to make the procedure simpler and safer by using an alternative to implantation: using an injectable pre-polymer liquid composite that cures quickly after injection adjacent to the DRG. They will compare an Injectrode-based system with traditional electrode stimulation at the DRG as an alternative to opioid administration. Researchers will perform benchtop characterization and refinement as a precursor to a clinical study, use modeling and animal testing to refine the efficiency of energy transfer from a transcutaneous electrical nerve stimulation unit to an Injectrode/Injectrode collector concept, and optimize the procedure for the complex anatomy of the human DRG.

Infants exposed to opioids during pregnancy can develop neonatal opioid withdrawal syndrome (NOWS). To date, clinicians generally use subjective evaluation to determine if an infant has NOWS, how severe the condition is, and if the infant needs treatment with or without medications. This project will evaluate whether an objective physiologic measure—continuous measurement of oxygen levels in the infant’s blood—can be used to develop a scoring system for assessing NOWS severity. The project will also develop and test a device to continuously monitor blood oxygen levels in the infants.

The Philippine Mollusk Symbiont International Cooperative Biodiversity Group harnesses the vast biodiversity of the Philippines to discover new drugs to treat bacterial infections, parasitic infections, pain, and other neurological conditions and cancer, all of which are serious health problems in both the Philippines and the United States. The Republic of the Philippines represents a unique nexus of exceptional biodiversity, dense human population with pressing societal needs, consequent urgent need for conservation, and government commitment to education and technology to harness national human and natural resources for a sustainable future. Mollusks are one of the most diverse groups of marine animals, and their associated bacteria represent an unexplored trove of chemical diversity. Researchers will use an increasing understanding of the interactions between mollusk symbionts and their hosts to discover the most novel and useful molecules. The project will document and describe Philippine mollusk biodiversity and support training and infrastructure that provide the foundation for conservation of Philippine biodiversity.

This project aims to validate Peptidase Inhibitor 16 (PI16) as a novel target for the treatment of chronic pain using mouse models and tissues of human patients with neuropathy. PI16 was identified as a novel regulator of chronic pain in preclinical bench studies. PI16 is a small molecule that has not been studied in the context of pain. Mice that are deficient for PI16 function are protected against mechanical allodynia (tactile pain from light touch) in spared nerve injury (SNI) and paclitaxel models of neuropathic pain. PI16 is only detectable in fibroblasts around peripheral nerves (perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons, glia or leukocytes. PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain. Increased PI16 secretion by DRG meningeal and perineurial fibroblasts may promote chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG.

Using neural tissues from pain patients, this project will investigate mechanisms of neuronal and/or immune dysfunction driving chronic pain. The researchers will use spatial transcriptomics on human dorsal root ganglion (DRG) and spinal cord tissues to examine the cellular expression profile for these targets using the 10X Genomics Visium technology. The use of tissues from control surgical patients and organ donors as well as surgical patients with neuropathic pain will enable validation of expression of these targets in human tissue as well as indication of their potential involvement in neuropathic pain. This collaborative effort will use DRGs removed from pain-phenotyped patients during neurological surgery, as well as lumbar DRGs and spinal cord from organ donors. This study will map the spatial transcriptomes at approximately single cell resolution in the human DRG and spinal cord.

Chronic pain from tissue injury often stems from long-term changes in spinal cord circuits that change nerve sensation. Reversing these changes may provide better pain therapeutics. Previous work in animal models showed that activating G protein-coupled receptor 37 (GPR37) dampens nerve signal intensity after long-term stimulation and alleviates pain behavioral responses. This project aims to validate GPR37 in the spinal cord as a useful target for new treatments for neuropathic pain. The work will facilitate screening and identification of new molecules that activate GPR37, which can then be tested for efficacy and safety in further research in animal models of pain.