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
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.
1R01NS116704-01	Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment	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	KAVELAARS, ANNEMIEKE; HEIJNEN, COBI J	Houston, TX	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: This project aims to validate Peptidase Inhibitor 16 (PI16) as a novel target for the treatment of chronic pain using mouse models and tissues of human patients with neuropathy. PI16 was identified as a novel regulator of chronic pain in preclinical bench studies. PI16 is a small molecule that has not been studied in the context of pain. Mice that are deficient for PI16 function are protected against mechanical allodynia (tactile pain from light touch) in spared nerve injury (SNI) and paclitaxel models of neuropathic pain. PI16 is only detectable in fibroblasts around peripheral nerves (perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons, glia or leukocytes. PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain. Increased PI16 secretion by DRG meningeal and perineurial fibroblasts may promote chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG.
1R01NS116759-01	Validating ASCT2 for the Treatment of Chronic Postsurgical Pain	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: Pain associated with surgery is experienced by millions of patients every year. Although post-surgical pain usually resolves as the surgical site heals, up to half of the patients develop chronic pain after surgery. Opioids remain the mainstay treatment for post-surgical pain which are fraught with serious side-effects and abuse liabilities. The endogenous mechanism that leads to the resolution of post-surgical pain remain unclear, specifically the effects of surgery on the metabolism of sensory neurons and how those changes influence the resolution of post-surgical pain are not known. Preliminary findings suggest that surgical trauma suppresses pyruvate oxidation while increased glutamine catabolism was associated with the resolution of post-surgical pain. This project will test the hypothesis that tissue incision and surgery disrupt the expression of the glutamine transporter ASCT2, which then prevents the resolution of post-incisional pain and aims to validate ASCT2 as a therapeutic target. This project will also employ pharmacological, genetic and animal pain model studies test a novel RNA expression-based strategy to enhance ASCT2 expression in DRG sensory neurons and alleviate postoperative pain in animal model systems. Successful completion of this project would validate ASCT2 as a novel endogenous non-opioid and non-addictive mechanism-based target for the resolution of postoperative pain.
1R01NS117340-01	B Lymphocyte-Mediated Autoimmunity in Pain After Trauma	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	PALO ALTO VETERANS INSTIT FOR RESEARCH	CLARK, DAVID J	Palo Alto, CA	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: A major recent advancement for the field of pain research is the recognition of immune system dysregulation as a contributor to the most serious adverse consequences of pain from injury. Accumulating data from clinical and laboratory studies place the activation of B lymphocytes at the center of much of this work, particularly with respect to chronic pain and disability-related outcomes. Validation of this B cell hypothesis could lead directly to trials testing the efficacy of novel or existing immunomodulating agents on posttraumatic pain. To achieve these goals a well-validated core mouse model of limb fracture will be employed with additional studies to be conducted in incisional and nerve injury models to broaden the assessment of B cell mediated effects on pain. Age and sex will be included as variables to enhance rigor.
1R01NS118504-01	Targeting GPCRs in Amygdalar and Cortical Neural Ensembles to Treat Pain Aversion	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIV OF NORTH CAROLINA CHAPEL HILL	SCHERRER, GREGORY	Chapel Hill, NC	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: There is a distinct neural ensemble in the brain that encodes the negative affective valence of pain. This project will identify novel targets to treat pain by determining the molecular identity of these BLA nociceptive cells via in situ hybridization and single cell RNAsequencing (scRNA-seq). Resolving the molecular identity of these ACC nociceptive cells will also reveal new targets to treat pain affect. To achieve these results the project will catalog candidate Gi/o-GPCR targets in BLA and ACC, test their utility to treat pain, and verify these new targets have no effect in the brain?s reward and breathing circuitry. The experiments in this project will also evaluate each target for abuse potential and effects on breathing by using behavioral assays for reward processing and whole-body plethysmography, respectively. To evaluate whether our results in rodents are likely to translate clinically, there will be an analysis of expression patterns of these drug targets in human tissue using in situ hybridization.
1R01NS118563-01A1	FKBP51 Antagonism to Prevent Chronic Pain: Optimizing Efficacy & Evaluating Safety and Mechanisms	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	UNIV OF NORTH CAROLINA CHAPEL HILL	LINNSTAEDT, SARAH ; MCLEAN, SAMUEL A	Chapel Hill, NC	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: A substantial proportion of Americans seeking emergency care after traumatic stress exposure (TSE) are at a high risk of chronic pain and opioid use/misuse. Physiologic systems involved in the stress response could possibly play a critical role in the development of chronic pain after TSE. FK506-binding protein 51 (FKBP51) is an intracellular protein known to affect glucocorticoid negative feedback inhibition and component of stress response, provides an important non-opioid therapeutic target for such chronic pain. This project will test the hypothesis that functional inhibition of FKBP51 prevents or reduces enduring stress-induced hyperalgesia in a timing, dose, and duration-dependent manner in animal models of single prolonged stress alone and in combination with surgery. This project will also test if FKBP51 inhibition enhances recovery following TSE via reduction in pro-inflammatory responses in peripheral and central tissues. It will also test whether FKBP51 inhibition effects cardiotoxicity or addiction. Completion of these studies will increase understanding of FKBP51 as a novel therapeutic target for the prevention of chronic pain and opioid use/misuse resulting from TSE.
1R01NS120663-01A1	Genetic and Pharmacological Validation of CRMP2 Phosphorylation as a Novel therapeutic Target for 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 ARIZONA	KHANNA, RAJESH	Tucson, 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: 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.
1R01NS131165-01A1	Validation of Neuropilin-1 Receptor Signaling in Nociceptive Processing	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NINDS	NEW YORK UNIVERSITY	KHANNA, RAJESH	New York, NY	2023
NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) NOFO Number: RFA-NS-22-034 Summary: Neuropilin 1 receptor (NRP1) is a protein receptor that is active in neurons and is hypothesized to be a key mediator of sensory neuron sensitization that can lead to pain. This project will study the cellular mechanisms by which NRP1 leads to sensitization and which cell types—sensory neurons, microglia, or both—are responsible for NRP1’s role in pain. The findings can help validate NRP1 in sensory neurons and the spinal cord as a target to treat pain following nerve injury.
1R21AT012304-01	Erythrocyte Autophagy Proteins as Potential Non-Opioid Novel Targets for Pain in Sickle Cell Disease	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NCCIH	UNIVERSITY OF ILLINOIS, CHICAGO	RAMASAMY, JAGADEESH	Chicago, IL	2022
NOFO Title: Emergency Awards: HEAL Initiative-Early-Stage Discovery of New Pain and Opioid Use Disorder Targets Within the Understudied Druggable Proteome (R21 Clinical Trial Not Allowed) NOFO Number: TR22-011 Summary: Sickle cell disease is an inherited blood disorder affecting about 100,000 Americans and over 20 million people worldwide. It is caused by a mutation in the gene for beta-globin that results in the characteristic sickled shape of red blood cells, life-long severe pain, and shortened lifespan. Painful episodes that require hospitalization and, in many cases, opioid treatment, are a hallmark of sickle cell disease. The source of these painful episodes remains unclear, and it is also unknown why pain severity varies so much among affected individuals. This project will identify novel, non-opioid targets to reduce sickle cell-related pain and search for biomarkers to help clinicians predict which individuals are at risk for increased pain, thereby improving health outcomes for people with sickle cell disease.
1R21DA057500-01	G Alpha Z Subunit as a Potential Therapeutic Target to Modulate Mu Opioid Receptor Pharmacology	Preclinical and Translational Research in Pain Management	Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain	NIDA	UNIVERSITY OF ROCHESTER	BIDLACK, JEAN M	Rochester, NY	2022
NOFO Title: Emergency Awards: HEAL Initiative-Early-Stage Discovery of New Pain and Opioid Use Disorder Targets Within the Understudied Druggable Proteome (R21 Clinical Trial Not Allowed) NOFO Number: TR22-011 Summary: Opioids affect the body by attaching to certain types of receptors that attach to G-proteins (particularly, a subtype called G-alpha). Opioids vary in their ability to provide pain relief as well as in their ability to require more drug to provide a response, known as tolerance. This project will explore the potential of various G-alpha subunits to increase or decrease opioid receptor signaling. The research findings will lay the groundwork for tailoring G-alpha related opioid effects to provide more pain relief while being less addictive.