Funded Projects

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Project # Sort descending	Project Title	Research Focus Area	Research Program	Administering IC	Institution(s)	Investigator(s)	Location(s)	Year Awarded
1DP2TR004354-01	Scale Up Single-Cell Technologies to Map Pain-Associated Genes and Cells Across the Lifespan	Cross-Cutting Research	Training the Next Generation of Researchers in HEAL	NCATS	Massachusetts General Hospital	SHU, JIAN	Boston, MA	2022
NOFO Title: Emergency Awards: HEAL Initiative- New Innovator Award (DP2 Clinical Trial Not Allowed) NOFO Number: RFA-tr-22-013 Summary: Current treatments for chronic pain, including opioids, are not effective for many individuals. Much remains unknown about genes, circuits, and cells that contribute to chronic pain, including how chronic pain changes across the lifespan in certain populations, including infants, children, older people, and pregnant women. This project will develop technology to map the genes, circuits, and cells associated with pain across ages, sexes, and during pregnancy. The technologies will guide the search for new biomarkers for chronic pain diagnosis and treatments.
1K24AR081143-01	Mentorship of Junior Investigators on HEAL-SKOAP	Clinical Research in Pain Management		NIAMS	JOHNS HOPKINS UNIVERSITY	Campbell, Claudia Michelle	Baltimore, MD	2021
NOFO Title: Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required) NOFO Number: PA-20-193 Summary: The HEAL-funded Sequenced-strategy for Improving Outcomes in People with Knee Osteoarthritis Pain (SKOAP) clinical trial evaluates behavioral, pharmacologic, and procedural interventions for patients with knee osteoarthritis pain. It is designed to mimic clinical care for these patients by first testing the effectiveness of conservative and nonsurgical interventions before considering surgical interventions. It is a large-scale clinical trial with a novel design that evaluates multidisciplinary treatments. Therefore, it offers a unique training opportunity for junior investigators from various disciplines who are interested in pain research and management. This mentoring award will allow a selected investigator to train junior investigators by providing protected, mentorship-focused time.
1K24AT011995-01	Providing training in effective non-opioid options for the treatment of pain conditions	Clinical Research in Pain Management		NCCIH	UNIVERSITY OF ILLINOIS AT CHICAGO	Doorenbos, Ardith Z	Chicago, IL	2021
NOFO Title: Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required) NOFO Number: PA-20-193 Summary: 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.
1K24NS126570-01	Mentorship in Precision Pain Medicine via the Early Phase Pain Investigation Clinical Network	Clinical Research in Pain Management		NINDS	Brigham and Women's Hospital	Edwards, Robert R	Boston, MA	2021
NOFO Title: Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required) NOFO Number: PA-20-193 Summary: Throughout clinical pain research, there is a need to increase the workforce of researchers familiar with individualized treatment strategies known as precision pain medicine. This mentoring award will leverage EPPIC-Net’s Clinical Coordinating Center resources to encourage interest in clinical pain management, in particular through multidisciplinary pain research projects. A selected clinician-researcher will mentor early career investigators and provide them with hands-on training activities and other skill-building experiences in clinical pain research, with a focus on precision pain medicine, biomarker development, and pain assessment. Mentoring activities will include formal educational coursework, inclusion in EPPIC-Net working groups, and collaborative writing experiences.
1K24NS126781-01	Mentoring in discovery and validation of clinical chronic pain biomarkers	Clinical Research in Pain Management		NINDS	STANFORD UNIVERSITY	Mackey, Sean C	Stanford, CA	2021
NOFO Title: Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required) NOFO Number: PA-20-193 Summary: Enhancing the workforce of pain investigators and practitioners is a key goal of the NIH HEAL Initiative. This mentoring award will allow a selected investigator to train early career investigators in patient-oriented research focusing on the development of diagnostic and prognostic biomarkers for high-impact chronic pain. Mentoring activities will include training in designing and implementing pain research studies, preparing scientific papers and presentations, writing successful grant applications, the responsible conduct of research, and successful navigation of the academic process to achieve scientific independence. This training will allow mentees to advance their independent careers as pain researchers.
1K24NS126861-01	Promoting high-quality chronic pain treatment trials through mentorship of junior investigators: A focus on study conduct and method development	Clinical Research in Pain Management		NINDS	UNIVERSITY OF ROCHESTER	Gewandter, Jennifer	Rochester, NY	2021
NOFO Title: Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required) NOFO Number: PA-20-193 Summary: Enhancing the workforce of pain investigators and practitioners is a key goal of the NIH HEAL Initiative. This mentoring award leverages the resources at one of EPPIC-Net’s Specialized Clinical Centers to encourage interest in clinical pain management, in particular through multidisciplinary pain research projects. A selected investigator will train early career clinical researchers on how to develop and validate relevant pain measures and outcomes in chronic pain conditions, including chemotherapy-induced peripheral neuropathy and neuropathic chronic low back pain. Mentoring activities will include formal research and analysis, active inclusion in EPPIC-Net working groups, and collaborative writing experiences.
1OT2NS122680-01	A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of 80 mg o.d. of NRD135S.El Versus Placebo in Adult and Elderly Subjects with Painful Diabetic Peripheral Neuropathy (SERENDIPITY-I)	Clinical Research in Pain Management	Early Phase Pain Investigation Clinical Network (EPPIC-Net)	NINDS	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ROBINSON-PAPP, JESSICA	New York, NY	2021
NOFO Title: HEAL Initiative: EPPIC-Net Pain Research Asset Application (OT2) NOFO Number: OTA-20-008 Summary: People with diabetes are at risk for painful diabetic peripheral neuropathy. This pain may be experienced as burning, aching, hypersensitivity to touch, or simply as pain, and there are no currently FDA-approved medications that reduce its symptoms. This phase 2 clinical trial, through the EPPIC-NET program, will test a potential new treatment for painful diabetic peripheral neuropathy. The molecule, NRD135S.E1, is a lab-made version of a natural substance traditionally used to brew tea to treat a variety of indications, including pain, in a village in Siberia. In clinical studies, NRD135S.E1 was well tolerated by patients and showed clinically relevant pain relief. Testing within EPPIC-Net will use a master protocol, an innovative study design in which multiple treatments can be tested at the same time with fewer research participants.
1OT2NS122680-01	A 24-week Week Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects with Moderate to Severe Knee Osteoarthritis Pain.	Clinical Research in Pain Management	Early Phase Pain Investigation Clinical Network (EPPIC-Net)	NINDS	Massachussetts General Hospital	FAVA, MAURIZIO	Boston, MA	2021
NOFO Title: HEAL Initiative: EPPIC-Net Pain Research Asset Application (OT2) NOFO Number: OTA-20-008 Summary: This award funds EPPIC-NET’s first phase 2 clinical trial, testing the novel oral drug CNTX-6970 in patients with moderate to severe knee osteoarthritis pain. It will include 150 participants at EPPIC-Net sites across the United States. Preclinical studies of CNTX-6970, which binds effectively and dose-proportionally to C-C chemokine type 2 (CCR2) receptors, have demonstrated potent analgesia in multiple pain models, with no emergent safety issues. CNTX-6970 has effects both at an affected joint, as well as on neural signaling. Participants will be randomized to receive CNTX-6970, placebo, or a third pain medication and will be followed for 24 weeks.
1OT2NS122680-01	A Randomized, Double-blind, Placebo-controlled, Parallel, 20-week, Phase 2b Study of Topical Pirenzepine (WST-057) or Placebo in Type 2 Diabetes Mellitus Patients with Painful Diabetic Peripheral Neuropathy	Clinical Research in Pain Management	Early Phase Pain Investigation Clinical Network (EPPIC-Net)	NINDS	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ROBINSON-PAPP, JESSICA	New York, NY	2021
NOFO Title: HEAL Initiative: EPPIC-Net Pain Research - Application for Clinical Trial and Related Activities (OT2) NOFO Number: OTA-20-008 Summary: People with diabetes are at risk for painful diabetic peripheral neuropathy. This pain may be experienced as burning, aching, hypersensitivity to touch, or simply as pain, and there are no currently FDA-approved medications that reduce its symptoms. This phase 2 clinical trial, through the EPPIC-NET program, will test a potential new treatment for painful diabetic peripheral neuropathy. The treatment, WST-057 (topical pirenzepine 4%), is a molecule that was developed in the 1980s and marketed throughout Europe and Asia in an oral form to treat gastric ulcers. Studies show that this type of molecule can increase the density of certain nerve fibers, which has been linked with improve patient-reported outcome measures for painful diabetic peripheral neuropathy.
1R01AR077890-01	Validation of Novel Target for OA Treatment	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIVERSITY OF ILLINOIS AT CHICAGO	SAMPEN, HEE-JEONG IM; LASCELLES, DUNCAN	Chicago, IL	2020
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: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability. Current challenges of managing OA are that there is no OA disease-modifying drug available, there are few effective treatment strategies, and there is an over-reliance on the use of opioids to manage OA-related joint pain. This project aims to validate vascular endothelial growth factor receptors 1 and 2 (VEGFR 1 receptor = Flt1) and (VEGFR 2 receptor = Flk1) as novel therapeutic targets for OA. This is based on a hypothesis that blocking these two specific receptors of VEGF will inhibit cartilage tissue degeneration and alleviate pain symptoms. This study will test the role of VEGFR-1 and -2 in multiple OA animal models using multiple available VEGF inhibitor molecules. The findings from these studies will develop a rationale for future clinical trials to target VEGFR-1 and -2 for OA patients and develop a novel non-addictive treatment for both joint pain and OA pathology.
1R01CA249939-01	Identification of Novel Targets for the Treatment of Chemotherapy-Induced Painful Peripheral Neuropathy	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIVERSITY OF MARYLAND BALTIMORE	MELEMEDJIAN, OHANNES KEVORK	Baltimore, MD	2020
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: Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN accounts for significant dose reductions and/or discontinuation of these life-saving treatments. Unfortunately CIPN can also persist in cancer-survivors, adversely affecting their quality of life. CIPN is not well-managed with existing pain therapeutics. Recent preliminary findings suggest that the transcription factor hypoxia-inducible factor alpha (HIF1A) is the target for the chemotherapeutic bortezomib, a proteasome inhibitor. This project will test the hypothesis that bortezomib chemotherapy-induced expression of HIF1A, PDHK1 and LDHA constitute an altered metabolic state known as aerobic glycolysis (AG) that leads to the initiation and maintenance of peripheral neuropathy and pain using a novel tumor-bearing animal model of CIPN. This project aims to validate HIF1A as a therapeutic target for the prevention of CIPN, as well as validate PDHK1 and LDHA as non-opioid therapeutic targets for chronic or established CIPN in animal models.
1R01DE029074-01A1	Novel Target Identification for Treatment of Chronic Overlapping Pain Using Multimodal Brain Imaging	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIVERSITY OF MARYLAND BALTIMORE	TRAUB, RICHARD J; MELEMEDJIAN, OHANNES KEVORK	Baltimore, MD	2020
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: As many as 64% of patients with Temporomandibular Joint Disorders (TMJDs) report symptoms consistent with Irritable Bowel Syndrome (IBS). However the underlying connection between these comorbid conditions is unclear and treatment options are poor. As such, pain management for these Chronic Overlapping Pain Conditions (COPCs) is a challenge for physicians and patients. This project will determine whether the convergence of pain from different peripheral tissues and perceived stress occurs in the brain and elicits a change in central neural processing of painful stimuli. This project will identify and validate specific lipids, enzymes and metabolic pathways that change expression in the brain during the transition from acute to chronic overlapping pain that can be therapeutically targeted to treat COPCs. Multi-disciplinary approaches will be used to combine brain imaging, visualization of spatial distribution of molecules, genetics, pharmacological and behavioral research techniques.
1R01DE029187-01	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.
1R01DE029202-01	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.
1R01DE029342-01	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.
1R01DE029951-01	Targeting Endosomal Receptors for Treatment of Chronic Pain	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	COLUMBIA UNIVERSITY HEALTH SCIENCES	BUNNETT, NIGEL W; SCHMIDT, BRIAN L	New York, NY	2020
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: Many non-opioid drugs target G Protein-Coupled Receptors (GPCRs), a family of proteins involved in many pathophysiological processes including pain, fail during clinical trials for unknown reasons. A recent study found GPCRs not only function at the surface of nerve cells but also within a cell compartment called the endosome, where their sustained activity drives pain. This study will build upon this finding and test whether the clinical failure of drugs targeting plasma membrane GPCRs is related to their inability to target and engage endomsomal GPCRs (eGPCRs). This study will use stimulus-responsive nanoparticles (NP) to encapsulate non-opioid drugs and selectively target eGPCR dyads to investigate how eGCPRs generate and regulate sustained pain signals in neuronal subcellular compartments. This study will also validate eGCPRs as therapeutic targets for treatment of chronic inflammatory, neuropathic and cancer pain. Using NPs to deliver non-opioid drugs, individually or in combinations, directly into specific compartments in nerve cells could be a potential strategy for new pain therapies.
1R01DE032501-01	Targeting HB-EGF and Trigeminal EGFR for Oral Cancer Pain and Opioid Tolerance	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NIDCR	NEW YORK UNIVERSITY	YE, YI	New York, NY	2022
NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) NOFO Number: NS22-034 Summary: Oral cancers are painful and often require use of opioid medications to manage pain. However, the effectiveness of opioids often wanes quickly, and many patients require higher doses because they develop tolerance to these medications. This project will study the potential value of blocking epidermal growth-factor receptors interacting with peripheral nerves to treat oral cancer pain. The findings will advance understanding of the molecular mechanisms underlying oral cancer pain and provide a rationale for repurposing epidermal growth-factor receptor blockers, which is already approved for head and neck cancer treatment for treating oral cancer and associated pain.
1R01DK123138-01	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
1R01DK134989-01	Signal Integration by Specialized Mesenchyme in Urothelial Homeostasis and Interstitial Cystitis/Bladder Pain Syndrome	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NIDDK	STANFORD UNIVERSITY	BEACHY, PHILIP A	Redwood City, CA	2022
NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) NOFO Number: NS22-034 Summary: Interstitial cystitis/bladder pain syndrome is a debilitating disease affecting many women. Opioid-based pain management is a common feature of current treatment approaches but is associated with the risk of addiction. The causes of this disorder remain unknown, and no effective treatments are available. This project will provide new insights using genetic, medication-based and other approaches in a mouse model, along with single-cell gene expression studies conducted with cells from mice and human patients who have this condition. The analyses will help provide targeted, safe, and effective treatment approaches for individuals with interstitial cystitis/bladder pain syndrome.
1R01DK135076-01	PNPase Inhibition as an Effective Treatment for Chronic Bladder Pain	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NIDDK	UNIVERSITY OF PITTSBURGH AT PITTSBURGH	BIRDER, LORI A (contact); JACKSON, EDWIN KERRY	Pittsburgh, PA	2022
NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) NOFO Number: NS22-034 Summary: Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome, are among the most difficult types of pain to treat. This project will conduct a detailed analysis of an enzyme thought to be involved with the disorder (purine nucleoside phosphorylase, or PNPase) as a target for new nonopioid pain medications to treat interstitial cystitis/bladder pain syndrome. The research will lay the groundwork for developing targeted treatments for visceral pain disorders.
1R01HD110922-01	CMG2 as a Target for Safe and Effective Treatment of Endometriosis-Associated Pain	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NICHD	BOSTON CHILDREN'S HOSPITAL	ROGERS, MICHAEL SEAN	Boston, MA	2022
NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) NOFO Number: NS22-034 Summary: Endometriosis is an often-painful disorder in which uterine tissue grows outside the uterus. Treatment of endometriosis-associated pain involves use of opioids in many women. This project aims to study a culprit gene thought to be involved with the disorder (capillary morphogenesis gene or CMG2) as a target for new, nonopioid pain medications. The research will also clarify how CMG2 s affects endometriosis-associated pain to test the effects of new medications for endometriosis pain.
1R01NS103350-01A1	Regulation of Trigeminal Nociception by TRESK Channels	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	WASHINGTON UNIVERSITY	CAO, YUQI	St. Louis, MO	2018
NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed) NOFO Number: NOT-NS-18-073 Summary: 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.
1R01NS113243-01	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.
1R01NS113257-01	Discovery and validation of a novel orphan GPCR as a target for therapeutic intervention in neuropathic pain	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	St. Louis University	SALVEMINI, DANIELA	St. Louis, MO	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: Neuropathic pain conditions are exceedingly difficult to treat, and novel non-opioid analgesics are desperately needed. Receptomic and unbiased transcriptomic approaches recently identified the orphan G-protein coupled receptor (oGPCR), GPR160, as a major oGPCR whose transcript is significantly increased in the dorsal horn of the spinal cord (DH-SC) ipsilateral to nerve injury, in a model of traumatic nerve-injury induced neuropathic pain caused by constriction of the sciatic nerve in rats (CCI). De-orphanization of GPR160 led to the identification of cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand which activates pathways crucial to persistent pain sensitization. This project will test the hypothesis that CARTp/GPR160 signaling in the spinal cord is essential for the development and maintenance of neuropathic pain states. It will also validate GPR160 as a non-opioid receptor target for therapeutic intervention in neuropathic pain, and characterize GPR160 coupling and downstream molecular signaling pathways underlying chronic neuropathic pain.
1R01NS116694-01	Validation of Spinal Neurotensin Receptor 2 as an Analgesic Target	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIVERSITY OF ARIZONA	PATWARDHAN, AMOL M	Tuscon, AZ	2020
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: Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative pain after major abdominal/thoracic surgeries. Contulakin G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans in preliminary studies. A small pilot study demonstrated CGX?s analgesic effect in some patients with spinal cord injury-associated pain. Preliminary findings from mechanistic studies in rodents identified neurotensin receptor 2 (NTSR2) as the mediator for analgesic effects of CGX. This project aims to validate spinal NTSR2 as an analgesic target utilizing three species (rat, mice and human), and two pain models (neuropathic pain and post-surgical pain). The project will utilize pharmacological and gene editing tools such as CRISPR-Cas9 and will include assessment of both sensory and affective measures of pain. A two-site parallel confirmation study is designed based on multisite clinical trials to further authenticate spinal NTSR2 as an analgesic target. Successful completion of this project could lead to the development of a non-opioid spinal analgesic that has high translational potential.