Funded Projects

This project aims to develop a next-generation noninvasive neuromodulation system for non-addictive pain treatments. The research team will build an integrated system that uses magnetic resonance image-guided focused ultrasound (MRgFUS) stimulation to target pain regions and circuits in the brain with high precision. The system will use MR imaging to locate three pain targets commonly used in clinical pain treatments, to stimulate those targets with ultrasound, and to monitor responses of nociceptive pain circuits using a functional MRI readout. Three collaborating laboratories will tackle the goals of this project: (Aim 1) Develop focused ultrasound technology for neuromodulation in humans, compatible with the high magnetic fields in an MRI scanner. (Aim 2) Develop MRI technology to find neuromodulation targets, compatible with focused ultrasound transducers. (Aim 3) Validate the complete MRgFUS neuromodulation system in brain pain regions in nonhuman primates. By the end of the project, the research team will have a fully developed and validated MRgFUS system that is ready for pilot clinical trials in pain management.

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.

There is currently no recognized way of accurately predicting who will recover from post-traumatic headache (PTH) during the acute phase following concussion and who will go on to develop persistent post-traumatic headache (PPTH), a condition that is difficult to treat effectively. Clinical experience suggests that early treatment is most effective, before headache patterns become persistent, but treating all patients with PTH would expose some patients to unnecessary treatment. Clinicians lack the information needed to make informed treatment decisions. Therefore, the study goals are to develop a prognostic biomarker signature for PPTH using clinical data and structural and functional brain neuroimaging and to assess the predictive accuracy of an ensemble biomarker signature for the early identification of patients at high risk for PPTH. This study can be translated into clinical practice and integrated into PTH clinical trials for early identification of those individuals who are at high risk for PPTH.

An International Cooperative Biodiversity Group with an interdisciplinary leadership team of physicians, pharmacologists, evolutionary biologists, and chemists will discover and develop therapeutic agents produced by Brazilian symbiotic bacteria. The team will target three therapeutic areas: 1) infectious fungal pathogens, 2) Chagas disease and leishmaniasis, and 3) cancers of the blood. All three areas represent major threats to human health that need to be addressed with new therapeutic agents. Internationally, invasive fungal diseases kill more people than malaria or TB, while Chagas disease imposes a special burden on Brazil, killing as many Brazilians as TB. Leishmaniasis has now passed Chagas disease in the Brazilian population. Despite major improvements in cancer chemotherapy, cancer is projected to result in 8 million deaths internationally this year (13% of all deaths, WHO) and an estimated 13 million per year by 2030.

Functional selectivity is a term used to describe the ability of drugs to differentially regulate the activity of multiple signaling cascades coupled to the receptor. The underlying mechanism for functional selectivity is based upon the formation of ligand-specific receptor conformations that are dependent upon ligand structure. Functional selectivity has the potential to revitalize the drug discovery/development process. Ligands with high efficacy for specific signaling pathways (or specific patterns of signaling) that mediate beneficial effects, and with minimal activity at pathways that lead to adverse effects, are expected to have improved therapeutic efficacy. We propose to demonstrate that ligand efficacy for specific signaling pathways associated with antinociception can be finely tuned by structural modifications to a ligand. We propose to use U50,488 and Salvinorin-A (Sal-A) as scaffolds to develop functionally selective analogs that maintain high efficacy for signaling pathways that lead to antinociception and minimize activity toward anti-antinociceptive signaling pathways.

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.

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.

Spinal cord injury (SCI) impairs sensory transmission and leads to chronic, debilitating neuropathic pain. While our understanding of the development of chronic pain has improved, the available therapeutics provide limited relief. We will examine the peripheral immune and inflammatory response. Secondary inflammation in response to SCI is a series of temporally ordered events: an acute, transient upregulation of chemokines, followed by the recruitment of monocytes/macrophages and generation of an inflammatory environment at the lesion site in the spinal cord, but also surrounding primary nociceptors in the dorsal root ganglia (DRG). These events precede neuropathic pain development. Previous work indicates that after SCI, macrophage presence in the DRG correlates with neuropathic pain. We propose to study: 1) whether the phenotype of macrophages that infiltrate the DRG is different than those that persist chronically after SCI and 2) how manipulation of macrophage phenotype affects nociceptor activity and pain development.

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.

There is an urgent need to find new ways to treat chronic pain through better targeting of underlying biological processes. Research shows that flexible synapses within the amygdala brain region play a role in the progression of pain from acute to chronic, but the details are not fully understood. The receptor glutamate delta 1 helps to form and maintain synapses in the amygdala in inflammatory and neuropathic pain. This project will study how the shape and characteristics of glutamate delta 1 affect pain conditions that involve the amygdala, toward informing future development of pain medications. 

Osteoarthritis is a degenerative joint disease marked by progressively worsening chronic joint pain that affects function and quality of life. Non-opioid, alternative medications are needed for people with this condition. Joint inflammation, damage, and pain involve signaling through the interleukin-6/glycoprotein 130 pathway. This project will test blocking this pathway in rodents with a new molecule with improved drug-like properties, toward developing an oral medication for osteoarthritis. 

This project will use a variety of state-of-the-art technologies to generate a comprehensive  gene expression map of human peripheral nerves. The research will enhance understanding about genes involved in various painful conditions associated with nerve damage (neuropathies) resulting from injury or disease. This research will analyze DNA sequences of individual neuronal and non-neuronal cells in human nerve cells (from individuals with and without pain located outside the spinal cord that are involved in pain signal transmission. The findings, together with other imaging and computational approaches, will be used to generate a spatial atlas of the human dorsal root ganglia – a key hub for pain communication between the brain and spinal cord.

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.