Funded Projects
Explore our currently funded projects. You may search with all three fields, then focus your results by applying any of the dropdown filters. After customizing your search, you may download results and even save your specific search for later.
Project # | Project Title | Research Focus Area | Research Program | Administering IC | Institution(s) | Investigator(s) | Location(s) | Year Awarded |
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1U18EB029353-01
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Development of a Wireless Endovascular Nerve Stimulator for Treatment of Refractory Neuropathic Pain | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NIBIB | BAYLOR COLLEGE OF MEDICINE | KAN, PETER TZE MAN; ROBINSON, JACOB T; SHETH, SUNIL | Houston, TX | 2019 |
NOFO Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
NOFO Number: RFA-EB-18-003 Summary: For patients with neuropathic pain refractory to therapy using small molecules, modulation of specific neural structures in the central or peripheral nervous system can provide effective alternative treatments. While current Food and Drug Administration–approved devices for dorsal root ganglion (DRG) stimulation are safe and effective, there have been an unfortunate number of adverse events associated with pulse generator infections and lead migration. The research team will develop a wireless, millimeter-sized nerve stimulator that can be delivered through the vasculature and stimulate the DRG to alleviate symptoms of neuropathic pain and the associated minimally invasive delivery method. This endovascular nerve stimulation (EVNS) system depends on development and integration of key novel technologies into an endovascular stent. The magnetoelectric transducers and electronic circuits will convert wireless power and data into stimulus patterns that can trigger neural activity in the DRG via miniature electrodes. After chronic demonstration of safety and functionality in large animal models, the team will prepare for regulatory discussions with the FDA. If successful, the EVNS will provide a technology platform for treating other neuropathic pain syndromes. |
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5R01NS104295-03
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Cellular and Molecular Role of CXCR4 signaling in Painful Diabetic Neuropathy | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NINDS | Northwestern University | MENICHELLA, DANIELA M | Evanston, IL | 2019 |
NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073 Summary: 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. |
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1R61NS113316-01
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Discovery and analytical validation of Inflammatory bio-signatures of the human pain experience | Preclinical and Translational Research in Pain Management | Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions | NINDS | THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON | PROSSIN, ALAN RODNEY | Houston, TX | 2019 |
NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041 Summary: Postoperative pain is a major contributor to the current opioid epidemic. Novel objective measures capable of personalizing pain care will enhance medical precision in prevention and treatment of postoperative pain. This project seeks to discover and validate a novel biosignature of the human pain experience, based on underlying IL-1 family cytokine activity and associated brain endogenous opioid function, that is readily quantifiable and clinically translatable to prevention and treatment of postoperative pain states. Specific aims will assess whether the novel biosignature will predict 1) experimentally induced pain during an experimental nociceptive pain challenge; 2) postoperative pain states with accuracy >75%, accounting for a wide range of variance in the human pain experience; and 3) postoperative pain states in an expanded clinically enriched sample. |
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1UH3NS115631-01
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Multisite adaptive brain stimulation for multidimensional treatment of refractory chronic pain | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NINDS | UNIVERSITY OF CALIFORNIA, SAN FRANCISCO | SHIRVALKAR, PRASAD | San Francisco, CA | 2019 |
NOFO Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-19-018 Summary: The research team will develop stimulation control algorithms to treat chronic pain using a novel device that allows longitudinal intracranial signal recording in an ambulatory setting. Subjects with refractory chronic pain syndromes will undergo bilateral surgical implant of temporary electrodes in the thalamus, anterior cingulate, prefrontal cortex, insula, and amygdala to identify candidate biomarkers of pain and optimal stimulation parameters. Six patients will proceed to chronic implantation of “optimal” brain regions for long-term recording and stimulation. The team will first validate biomarkers of low- and high-pain states to define neural signals for pain prediction in individuals. They will then use these pain biomarkers to develop personalized closed-loop algorithms for deep-brain stimulation (DBS) and test the feasibility of closed-loop DBS for chronic pain in weekly blocks. Researchers will assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS or sham in a double-blinded cross-over trial and measure mechanisms of DBS tolerance. |
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1R01DE029342-01
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Identification and Validation of a Novel Central Analgesia Circuit | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NIDCR | DUKE UNIVERSITY | WANG, FAN | Durham, NC | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: This project focuses on identifying and validating a new central analgesic circuit in the brain, based on a highly innovative hypothesis that the strong analgesic effects of general anesthesia (GA) are in part carried out by GA-mediated activation of the endogenous analgesic circuits. Preliminary discovery studies found that a subset of GABAergic neurons located in the central amygdala (CeA) become strongly activated and express high levels of the immediate early gene Fos under GA (hereafter referred to as CeAGA neurons). Furthermore, activation of these neurons exert profound pain-suppressing effects in an acute pain model and a chronic orofacial neuropathic pain model in mice. Based on these exciting preliminary findings, this project will identify and validate CeAGA neurons’ analgesic functions utilizing multiple mouse pain models. Identification of these shared common pathways that need to be suppressed by specific subtypes of CeAGA analgesic neurons will be highly critical for developing precise CeAGA-targeted therapies to treat chronic pain. |
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1R01NS113243-01
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Targeting sensory ganglia and glial signaling for the treatment of acute and chronic pain | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NINDS | UNIVERSITY OF CINCINNATI | BERTA, TEMUGIN | Cincinnati, OH | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: 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. |
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1R61NS113315-01
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Biomarker Signature to Predict the Persistence of Post-Traumatic Headache | Preclinical and Translational Research in Pain Management | Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions | NINDS | MAYO CLINIC ARIZONA | CHONG, CATHERINE DANIELA | Scottsdale, AZ | 2019 |
NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041 Summary: 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. |
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1UH3NS115118-01
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Transcranial focused ultrasound for head and neck cancer pain. A pilot study | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NINDS | UNIVERSITY OF VIRGINIA | ELIAS, WILLIAM JEFFREY | Charlottesville, VA | 2019 |
NOFO Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-19-018 Summary: Head and neck cancer is particularly susceptible to nociceptive and neuropathic pains because it is dense with sensitive anatomic structures and richly innervated. Transcranial magnetic resonance imaging–guided focused ultrasound (FUS) is a new stereotactic modality capable of delivering high-intensity energy through the intact human skull with submillimeter precision. This clinical trial will target the spinothalamic and spinoreticular pain circuits by unilateral FUS mesencephalotomy, an effective procedure for cancer pain but limited by the accuracy of its era. The primary aim is to assess the safety and preliminary effectiveness in six head and neck cancer patients with opioid-resistant pain. Researchers will investigate the potential mechanism of pain relief as the mesencephalotomy target involves the confluence of the ascending and descending pain systems. Aims 2 and 3 will investigate these systems with electrophysiology specific for the spinothalamic tract and carfentenil positron emission tomography imaging that measures the brain’s endogenous opioids. |
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1U18EB029354-01
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Treating pain in sickle cell disease by means of focused ultrasound neuromodulation | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NIBIB | CARNEGIE-MELLON UNIVERSITY | HE, BIN | Pittsburgh, PA | 2019 |
NOFO Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
NOFO Number: RFA-EB-18-003 Summary: Researchers will develop a novel transcranial focused ultrasound (tFUS) device for pain treatment and establish its effectiveness for treating sickle cell disease (SCD) pain in humanized mice. The tFUS will target the specific cortical regions involved in SCD pain using a novel non-invasive electrophysiological source imaging technique. The project’s goals have several aims. Aim 1: Develop tFUS devices for pain treatment. The mouse-scale system will be designed to validate the therapeutic effect of stimulating the anticipated cortical targets. This will inform development of the simpler human-scale system, which will use models of the skull to select cost-effective transducers to reach the targets. Aim 2: Evaluate tFUS effectiveness and optimize stimulation parameters in an SCD mice model. Researchers will determine effective tFUS parameters to chronically reduce SCD pain in mice and validate this using behavioral measures. Aim 3: Use electrophysiological source imaging to target and trigger closed-loop tFUS in animal models. This aim also includes performing safety studies to prepare for human trials. The project will develop a transformative, noninvasive tFUS device to effectively and safely treat pain in SCD. |
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1R01DE029202-01
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Validation of blocking TSP4/Cava2d1 interaction as a new target for neuropathic pain | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NIDCR | UNIVERSITY OF CALIFORNIA-IRVINE | LUO, ZHIGANG DAVID | Irvine, CA | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: Validation of novel pain targets is a critical step toward the development of new non-addictive therapeutic agents for chronic pain management. Recent findings suggest that nerve injury-induced concurrent upregulation of the calcium channel alpha-2delta-1 subunit (CaValpha-2-delta-1) and thrombospondin-4 (TSP4) proteins in sensory and spinal cord neurons contributes to neuropathic pain development. Specifically, induction of aberrant excitatory synapse formation and sensitization of neurotransmission in spinal cord underlies this process; accordingly, a target site has been identified in the TSP4 that plays a critical role in mediating these pathological changes upon interaction with the CaValpha-2-delta-1 protein. This project will validate this novel target site in TSP4 for development of non-addictive pain medications, utilizing multidisciplinary approaches to investigate if blocking and genetic deletion of the target site can block or prevent the development of chronic pain state, aberrant excitatory synapse formation, and spinal cord neuron sensitization after injury in multiple rodent neuropathic pain models. |
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1UG3TR003150-01
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Human Microphysiological Model of Afferent Nociceptive Signaling | Preclinical and Translational Research in Pain Management | Translational Research to Advance Testing of Novel Drugs and Human Cell-Based Screening Platforms to Treat Pain and Opioid Use Disorder | NCATS | TULANE UNIVERSITY OF LOUISIANA | MOORE, MICHAEL J (contact); ASHTON, RANDOLPH S; RAJARAMAN, SWAMINATHAN | New Orleans, LA | 2019 |
NOFO Title: HEAL Initiative: Tissue Chips to Model Nociception, Addiction, and Overdose (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-TR-19-003 Summary: This project will develop a human cell-based model of the afferent pain pathway in the dorsal horn of the spinal cord. The research team’s approach utilizes novel human pluripotent stem cell (hPSC)-derived phenotypes in a model that combines 3D organoid culture with microfabricated systems on an integrated, three-dimensional (3D) microelectrode array. Researchers will establish the feasibility of a physiologically relevant, human 3D model of the afferent pain pathway that will be useful for evaluation of candidate analgesic drugs. They will then improve the physiological relevance of the system by promoting neural network maturation before demonstrating the system’s utility in modeling adverse effects of opioids and screening compounds to validate the model. Completion of the study objective will establish novel protocols for deriving dorsal horn neurons from hPSCs and create the first human microphysiological model of the spinal cord dorsal horn afferent sensory pathway. |
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1U44NS115692-01
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Development and Optimization of MNK Inhibitors for the Treatment of Neuropathic Pain | Preclinical and Translational Research in Pain Management | Development and Optimization of Non-Addictive Therapies to Treat Pain | NINDS | 4E THERAPEUTICS INC. | SAHN, JAMES JEFFREY | Austin, TX | 2019 |
NOFO Title: HEAL Initiative: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain - (U44 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-19-020 Summary: MNK-eIF4E signaling is activated in nociceptors upon exposure to pain or peripheral nerve injury, promoting cytokines and growth factors and increasing nociceptor excitability, which leads to neuropathic pain. Genetic or pharmacological inhibition of MNK signaling blocks and reverses nociceptor hyperexcitability as well as behavioral signs of neuropathic pain. A clinical phase drug for cancer shows strong specificity as an MNK inhibitor but requires optimization because MNK inhibition in the central nervous system (CNS) may lead to depression, an unacceptable side effect for a neuropathic pain drug. The research team plans a targeted medicinal chemistry and screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment with the goal of restricting its CNS penetration while retaining potency, specificity, and in vivo bioavailability and efficacy. |
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3R01NS093990-04S1
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S1P RECEPTOR MECHANISMS IN NEUROPATHIC PAIN | Preclinical and Translational Research in Pain Management | NINDS | VIRGINIA COMMONWEALTH UNIVERSITY | SIM-SELLEY, LAURA J; HAUSER, KURT F; LICHTMAN, ARON H; SELLEY, DANA E | RICHMOND, VA | 2018 | |
NOFO Title: Mechanisms, Models, Measurement, & Management in Pain Research (R01)
NOFO Number: PA-13-118 Summary: Chronic pain diminishes the quality of life for millions of patients, and new drugs that have better efficacy and/or fewer side effects are needed. A promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates central nervous system (CNS) neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY), acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). We propose that the S1P1 receptor is a target for treatment of neuropathic pain. We will test whether S1P1 receptors mediate anti-hyperalgesic effects in a mouse neuropathic pain model. The specific aims are to: 1) determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY. |
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1R61NS114954-01
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The Inflammatory Index as a Biomarker for Pain in Patients with Sickle Cell Disease | Preclinical and Translational Research in Pain Management | Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions | NINDS | MEDICAL COLLEGE OF WISCONSIN | BRANDOW, AMANDA M | Milwaukee, WI | 2019 |
NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041 Summary: Debilitating pain is the most common complication of sickle cell disease (SCD), but there is significant variability in pain expression in these patients. Currently, there is no plasma biomarker that can prognosticate which patients are likely to experience pain. The overall goal of this proposed research is to develop a biomarker that prognosticates the clinical expression of pain in SCD. Project aims are to (1) derive the inflammatory index for pain by identifying inflammatory and immune regulatory gene probe sets that will distinguish healthy controls, patients with SCD in baseline health, and patients with SCD in acute pain and (2) determine whether co-expressed genes from patients with SCD correlate with clinical pain data. Subsequent aims are to (1) determine the clinically meaningful changes of the index in patients with SCD and (2) investigate the preliminary clinical validity of the index as a prognostic biomarker for pain in patients with SCD. |
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3U01DE025633-03S1
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INVESTIGATION AND MODULATION OF THE MU-OPIOID MECHANISM IN CHRONIC TMD (IN VIVO) | Preclinical and Translational Research in Pain Management | NIDCR | UNIVERSITY OF MICHIGAN AT ANN ARBOR | DASILVA, ALEXANDRE | ANN ARBOR, MI | 2018 | |
NOFO Title: Biology of the Temporomandibular Joint in Health and Disease (R01)
NOFO Number: PA-14-358 Summary: Initial studies using positron emission tomography (PET) with [11C] carfentanil, a selective radiotracer for ?-opioid receptor (?OR), have demonstrated that there is a decrease in thalamic µOR availability (non-displaceable binding potential BPND) in the brains of TMD patients during masseteric pain compared to healthy controls. ?-opioid neurotransmission is arguably one of the mechanisms most centrally involved in pain regulation and experience. The main goals of our study are: first, to exploit the ?-opioidergic dysfunction in vivo in TMD patients compared to healthy controls; second, to determine whether 10 daily sessions of non-invasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in TMD patients; and third, to investigate whether repetitive active M1 HD-tDCS induces/reverts ?OR BPND changes in the thalamus and other pain-related regions and whether those changes are correlated with TMD pain measures. |
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1RF1NS113840-01
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Nrf2 Activation for Addiction-Free Treatment of Neuropathic Pain | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NINDS | UNIVERSITY OF TX MD ANDERSON CAN CTR | GRACE, PETER MICHAEL | Houston, TX | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: Effective treatments are elusive for the majority of patients with neuropathic pain. Reactive oxygen and nitrogen species (ROS/RNS) are involved in neuropathic pain, because they drive mitochondrial dysfunction, cytokine production, and neuronal hyperexcitability; therefore, stimulation of endogenous antioxidants is predicted to simultaneously resolve multiple neuropathic pain mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is a potential therapeutic target because it regulates the expression of a large number of endogenous antioxidant-related genes and can be activated with a single drug. This project will test the hypothesis that Nrf2 activation increases multiple endogenous antioxidants, therefore reversing neuropathic pain behaviors and counteracting neuropathic pain mechanisms that are driven by ROS/RNS and could provide an effective pain therapy, with minimal abuse/addictive potential. |
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3R01DK103901-04S1
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TARGETING THE TRANSIENT RECEPTOR POTENTIAL CHANNELS TO IMPROVE BOWEL DYSFUNCTION | Preclinical and Translational Research in Pain Management | NIDDK | WASHINGTON UNIVERSITY | HU, HONGZHEN | SAINT LOUIS, MO | 2018 | |
NOFO Title: Research Project Grant (Parent R01)
NOFO Number: PA-13-302 Summary: Postoperative ileus (POI) following gastrointestinal (GI) surgery leads to significant patient morbidity and prolonged hospitalizations. Recent studies have demonstrated that intestinal manipulation and surgical trauma activate inflammatory macrophages (M?) and release inflammatory mediators such as nitric oxide (NO) to inhibit intestinal smooth muscle cells in POI. Intestinal M? are a highly heterogeneous and dynamic population in the innate immune system. Preliminary studies show that transient receptor potential vanilloid 4 (TRPV4) channel, a molecular sensor of tissue damage and inflammation, is exclusively expressed by the F4/80+/CD206+ intestinal anti-inflammatory M2 M?. Activation of TRPV4 produces an intestinal contractile response and improves GI transit in a mouse model of POI. The current proposal aims to elucidate the cellular and molecular mechanisms underlying the activation of TRPV4 in the intestinal M2 M?. |
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1U44NS115111-01
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High-Resolution, Spinal Cord Stimulation for Non-Opioid Treatment of Neuropathic Pain | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NINDS | MICRO-LEADS, INC. | MCLAUGHLIN, BRYAN L | Somerville, MA | 2019 |
NOFO Title: HEAL Initiative: Translational Devices to Treat Pain (U44 Clinical Trial Optional)
NOFO Number: RFA-NS-19-017 Summary: The research team will develop HD64—a high-resolution, 64-channel spinal cord stimulation therapy to provide more pain relief for those suffering from chronic neuropathic pain and opioid dependence. HD64 provides an ultra-thin conformal blanket of stimulation contacts across the width of the spinal cord and enables more precise targeting of the lateral structures of the spinal cord to enhance pain relief. A cadaveric pilot run followed by a non-significant risk intraoperative study will be performed to inform the design parameters of HD64 arrays. The study will evaluate activation of medial and lateral spinal targets. At the end of Phase 1, the clinical feasibility of HD64 surgical leads will be established. In Phase 2, researchers will develop an external active lead pulse generator and charger. They will perform an early feasibility study human trial using active HD64 and mechanical and electrical design verification testing and chronic safety studies in large animals. |
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1R01DK123138-01
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Validation of peripheral CGRP signaling as a target for the treatment of pain in chronic pancreatitis | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NIDDK | JOHNS HOPKINS UNIVERSITY | PASRICHA, PANKAJ J | Baltimore, MD | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: Chronic pancreatitis (CP) and the debilitating pain associated with it remains a common and challenging clinical syndrome that is difficult to treat effectively. Using rodent models of CP, preliminary studies have found that nerve growth factor (NGF) and transforming growth factor beta (TGFb) appear to be acting by the common effector, calcitonin-gene related peptide (CGRP), to induce pain in CP. CGRP is known to mediate pain as a neurotransmitter in the central nervous system, specifically as a potent vasodilator involved in migraine. This project will test the hypothesis that peripheral CGRP is a major mediator of peripheral nociceptive sensitization in CP, and that peripherally restricted anti-CGRP treatment could provide an efficient and sufficient approach for the treatment of pain in pancreatitis |
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5R01NS094461-04
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Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NINDS | UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANTONIO | SHAPIRO, MARK S | San Antonio, TX | 2018 |
NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073 Summary: Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of cellular signals. 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 AKAP79/150. We will probe complexes containing AKAP79/150 and three different channels critical to nervous function: KCNQ/Kv7, TRPV1, and CaV1.2. We will use"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. We hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which we will examine by patch-clamp electrophysiology of the neurons. Since all three of these channels bind to AKAP79/150, we hypothesize that they co-assemble into complexes in neurons and that they are dynamically regulated by other cellular signals. |
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1UG3NS115718-01
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Development of MRGPRX1 positive allosteric modulators as non-addictive therapies for neuropathic pain | Preclinical and Translational Research in Pain Management | Development and Optimization of Non-Addictive Therapies to Treat Pain | NINDS | JOHNS HOPKINS UNIVERSITY | TSUKAMOTO, TAKASHI | Baltimore, NC | 2019 |
NOFO Title: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-19-010 Summary: Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system; however, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. An intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. The goal of this study is to develop a CNS-penetrant small-molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions. |
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1R01DE029187-01
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LIGHT and Lymphotoxin targeting for the treatment of chronic orofacial pain conditions | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NIDCR | UNIVERSITY OF TEXAS HLTH SCIENCE CENTER | AKOPIAN, ARMEN N | San Antonio, TX | 2019 |
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043 Summary: Mismanagement of orofacial chronic pain, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, substantially contributes to opioid overuse; overdose-related deaths; and cardiovascular, renal, and neurological complications at epidemic proportions. The current paradigm implies that orofacial conditions could trigger maladaptation of the immune system and plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, provide a balance between protective immunity and immunopathology during chronic inflammatory diseases. This project will test the hypothesis that targeting LIGHT and LT? signaling could prevent the development and inhibit the maintenance of chronic pain produced by TMJD and oral cancer, via peripheral mechanisms involving plasticity of immune, stromal, and tumor cells, as well as sensory neurons. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain and offers new therapeutic targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer. |
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1U18EB029351-01
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Development of an MRgFUS system for precision-targeted neuromodulation of pain circuits with simultaneous functional MRI | Preclinical and Translational Research in Pain Management | Translating Discoveries into Effective Devices to Treat Pain | NIBIB | VANDERBILT UNIVERSITY MEDICAL CENTER | CASKEY, CHARLES F (contact); CHEN, LI MIN ; GRISSOM, WILLIAM A | Nashville, Tennessee | 2019 |
NOFO Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
NOFO Number: RFA-EB-18-003 Summary: 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. |
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3R01NS097880-02S1
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VALIDATION OF TARGETING MACROPHAGE-MEDIATED EVENTS IN THE DRG TO ALLEVIATE CHRONIC SPINAL CORD INJURY PAIN | Preclinical and Translational Research in Pain Management | Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain | NINDS | DREXEL UNIVERSITY | DETLOFF, MEGAN R | PHILADELPHIA, PA | 2019 |
NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591 Summary: 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. |
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3U19TW007401-14S1
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EXPLORATION, CONSERVATION, & DEVELOPMENT OF MARINE BIODIVERSITY IN FIJI AND THE SOLOMON ISLANDS | Preclinical and Translational Research in Pain Management | FIC | GEORGIA INSTITUTE OF TECHNOLOGY | HAY, MARK E | ATLANTA, GA | 2018 | |
NOFO Title: Limited Competition: International Cooperative Biodiversity Groups (U19)
NOFO Number: RFA-TW-13-001 Summary: This International Cooperative Biodiversity Group application aims to discover and develop small molecule drug leads from cultured marine microbes and diverse coral reef organisms collected from Fiji and the Solomon Islands. Drug discovery efforts will focus on four major disease areas of relevance to the United States and low- and middle-income countries: infectious disease, including tuberculosis and drug-resistant pathogens; neglected tropical diseases, including hookworms and roundworms; cancer; and neurodegenerative and central nervous system disorders. Screening in these therapeutic areas will be performed in collaboration with two major pharmaceutical companies, two highly respected academic groups, and various testing centers and government resources that are available to facilitate drug discovery and development. The acquisition of source material for this program will be linked to biotic surveys, informed by ecological investigations addressing the chemical mediation of biotic interactions, and enriched using ecology-based strategies designed to maximize secondary metabolite production and detection. |