Funded Projects

Peripheral nerve injury-induced upregulation of three axonal guidance phosphoproteins correlates with the development of neuropathic pain through an unidentified mechanism: 1) collapsin response mediator protein 2 (CRMP2); 2) the N-type voltage-gated calcium (CaV2.2); 3) the NaV1.7 voltage-gated sodium channel. Injury induced phosphorylated-CRMP2/CaV2.2 and phosphorylated-CRMP2/NaV1.7 upregulation in the sensory pathway may promote abnormal excitatory synaptic transmission in spinal cord that leads to neuropathic pain states. This project will validate CRMP2 phosphorylation as a novel target in neuropathic pain using innovative tools. Examples include a genetic approach (crmp2S522A) in mice as well as a non-opioid pharmacological approach (a novel CRMP2-phsphorylation targeting compound). Demonstrating that inhibition of CRMP2 phosphorylation reverses or prevents neuropathic pain will promote the discovery and validation of a novel therapeutic target (CRMP2-phosphorylation) to facilitate the development of novel pain therapeutics.

High-voltage-gated calcium channels convert electrical signals into physiological responses. After a nerve injury, levels of these channels go down in some neurons in the dorsal root ganglia that communicates pain signals to and from the brain. This decline results in reduced flow of calcium that may underlie pain. This project will develop novel approaches to block these calcium channels p to further study their roles in controlling pain.

The Data Coordinating Center (DCC) of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) will be the data and biospecimen manager for pain research within the HEAL Partnership. As such, it will host, manage, standardize, curate, and provide a sharing platform for data and biospecimens for HEAL initiatives, such as the Acute to Chronic Pain Signatures initiative and the BACPAC, in addition to EPPIC-Net studies. The DCC will develop and maintain a databank for depositing data, will link these data with a repository for biological samples, and will create a platform for teams to work together to analyze and interpret data. Further, the DCC will provide leadership in the statistical design and analysis of EPPIC-Net studies and will deploy advanced systems and processes for data collection, management, quality assurance, and reporting. The DCC will create, sustain, and continually advance a robust organization for the rapid design, implementation, and performance of high-quality rigorous Phase II clinical trials to test promising therapeutics for pain.

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this research. This research will focus on three different channels critical to nervous function. One is the"M-type" (KCNQ, Kv7) K+ channel that plays fundamental roles in the regulation of excitability in nerve and muscle. It is thought to associate with Gq/11- coupled receptors, protein kinases, calcineurin (CaN), calmodulin (CaM) and phosphoinositides via AKAP79/150. Another channel of focus is TRPV1, a nociceptive channel in sensory neurons that is also thought to be regulated by signaling proteins recruited by AKAP79/150. The third are L-type Ca2+ (CaV1.2) channels that are critical to synaptic plasticity, gene regulation and neuronal firing. This research will probe complexes containing AKAP79/150 and these three channels using"super-resolution" STORM imaging of primary sensory neurons and heterologously-expressed tissue-culture cells, in which individual complexes can be visualized at 10-20 nm resolution with visible light, breaking the diffraction barrier of physics. The researchers hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which the researchers will examine by patch-clamp electrophysiology of the neurons. Förster resonance energy transfer (FRET) will also be performed under total internal reflection fluorescence (TIRF) or confocal microscopy, further testing for complexes containing KCNQ, TRPV1 and CaV1.2 channels. Since all three of these channels bind to AKAP79/150, the researchers hypothesize that they co-assemble into complexes in neurons, together with certain G protein-coupled receptors. Furthermore, the researchers hypothesize these complexes to not be static, but rather to be dynamically regulated by other cellular signals, which the researchers will examine using rapid activation of kinases or phosphatases. Several types of mouse colonies of genetically altered AKAP150 knock-out or knock-in mice will be utilized.

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.

Chronic pain is maintained, in part, by persistent changes in sensory neurons, including a pathological increase in peptides derived from the neurosecretory protein VGF (non-acronymic). Preliminary findings show that the C-terminal VGF peptide, TLQP-62, contributes to spinal cord neuroplasticity and that TLQP-62 immunoneutralization attenuates established mechanical hypersensitivity in a traumatic nerve injury model of neuropathic pain. This project will test the hypothesis that spinal cord TLQP-62 signaling can be targeted for the development of new chronic pain treatments through immunoneutralization and/or receptor inhibition. It will pursue discovery and validation of TLQP-62-based therapeutic interventions along two parallel lines: identification of TLQP-62 receptor(s) and validation of anti-TLQP-62 antibodies as a potential biological therapeutic option for chronic neuropathic pain conditions.

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.

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.

The Greater New York Clinical Center (GNYCC) aims to engage experts in pain research and pain practice to build the infrastructure required to support the objectives of the Early Phase Pain Investigation Clinical Network (EPPIC-Net). The GNYCC will provide expertise and resources to perform phase 2 clinical trials to test the efficacy of novel pain treatments, as well as phenotyping and biomarker studies that will enable customized treatments. The consortium comprises four major academic centers in New York City, one of the most diverse cities in the United States and the nation’s largest metropolitan area. We will 1) build infrastructure to rapidly access clinical trial resources and a network of investigators and clinical leaders, 2) develop a plan for swift evaluation and launch of proposed studies, and 3) optimize patient retention and monitor sites to ensure protocol adherence, data quality, and efficiency.

Research shows that individuals with chronic pain may experience brain changes that contribute to anxiety, depression, and cognitive impairment. This project will test a user-friendly, home-based device to treat chronic pain. The device stimulates the brain through olfactory training: repetitive daily stimulation with specific smells. The research will optimize a treatment approach and test the device in a clinical study.

Spinal cord stimulators (SCS) and related devices are commonly used for hard-to-treat pain conditions, but how they work remains unclear. This knowledge is important for improving device design and stimulation patterns, as well as for determining which patients will benefit. Through a series of clinical studies in patients with SCS devices, this project will explore the hypothesis that SCS devices reduce pain by changing the excitability of peripheral sensory nerve fibers in the spinal cord. The results should guide development of biomarkers to advance research further.

Wound care procedures (WCPs), such as dressing changes, cause moderate to severe pain in 74% of patients, nearly half of whom experience severe pain. Mainstay recommendations to prevent pain during WCPs have focused on either administration of preventive and procedural analgesia or use of expensive, non-adherent dressings. However, it is unclear which patients to target for analgesia or expensive dressings, leading to their inappropriate over- or underuse. To achieve the aims of the study, a comprehensive set of wound, patient, and biological factors will be measured concurrently with pain during a dressing change among a sample of 450 inpatients with open wounds. A predictive model will be developed and biological mechanisms will be examined using logistic regression. The proposed study has the potential to make significant contributions because clinicians will be able to target those patients requiring preventive pain control, thereby eliminating the spiraling impact of painful procedures on nociceptor sensitization.

Opioid overdose deaths disproportionately affect Black individuals in the United States. While the use of complementary and integrative pain treatments is effective and widely recommended, Black pain patients (especially those who also have depression) face barriers to the use of these approaches. This project will refine, test, and prepare to implement a novel approach to overcoming these treatment barriers. The research will partner with and empower Black patients to find safe, effective pain treatments that best match their values, preferences, and lifestyles.