Funded Projects

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Project # Project Title Research Focus Area Research Program Administering IC Institution(s) Investigator(s) Location(s) Year Awarded
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.
3R01AT010773-02S1
Minor Cannabinoids and Terpenes: Preclinical Evaluation as Analgesics Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NCCIH RESEARCH TRIANGLE INSTITUTE WILEY, JENNY L. Research Triangle Park, NC 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

G-protein coupled receptor 3 (GPR3) is an orphan receptor present in the central nervous system (CNS) that plays important role in many normal physiological functions and is involved in a variety of pathological conditions. Although the brain chemical that activates this receptor has not been identified, work with GPR3 knockout mice has identified GPR3 as a novel drug target for several Central Nervous System (CNS) mediated diseases including neuropathic pain. However, despite the emerging behavioral implications of the GPR3 system, little is known about how GPR3 affects behavior due to the lack of potent and selective chemical probes that allow scientists to examine functioning of the receptor. Recently, two cannabinoid chemicals present in the cannabis plant were discovered as affecting GPR3. This study will modify the chemical structure of these compounds to increase their potency and selectivity so that they may be used as pharmacological tools to investigate the role of GPR3 in modulating pain. In addition, this project focuses on identifying new compounds that show promise for development into therapeutics for the treatment of pain.
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.
3R01AT010757-02S1
The study of Gpr149 in nociception and the peripheral action of minor cannabinoids Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NCCIH UNIVERSITY OF CALIFORNIA, SAN FRANCISCO HELLMAN, JUDITH San Francisco, CA 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

The cannabis plant contains many active compounds known collectively as cannabinoids that have been shown to possess analgesic and anti-inflammatory properties. These compounds exert their biological activity, in part, through the cannabinoid receptor. The cannabinoid receptor is a member of a class of proteins known as G-protein coupled receptors (GPCRs). This study will test whether a GPCR with unknown biological function, called Gpr149, has a role in the activity of cannabinoids. The study will identify and characterize Gpr149 expression in mouse cells, and deeply characterize the action of minor cannabinoids, endocannabinoids and products of inflammation to modulate Gpr149. This research will provide insight into the analgesic and anti-inflammatory action of minor cannabinoids and into the role of Gpr149 in nociception and the sensitization of nociceptors to inflammatory mediators.
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.
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.
3U44NS115692-01S1
Development and Optimization of MNK Inhibitors for the 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 4E THERAPEUTICS INC. SAHN, JAMES JEFFREY Austin, TX 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

There is an urgent unmet need for more efficacious analgesics that act via a non-opioid pathway. Mitogen Activated Protein Kinase-interacting kinase 2 (MNK2) is an enzyme that has been implicated in pain signaling, and there is compelling evidence that inhibiting MNK2 has significant pain-reducing effects with few side-effects. Since MNK2 selective inhibitors have not yet been identified, selective inhibition of MNK2 with a small molecule has not been possible. The development of such compounds will enable studies that will illuminate key differences between MNK2 and MNK1. More importantly, from a therapeutic standpoint, highly selective MNK2 inhibitors may prove to have enhanced efficacy and a more favorable side-effect profile than molecules that inhibit both MNK2 and MNK1. This project will support the design and synthesis of at least one MNK2 inhibitor, with >100-fold selectivity over MNK1, that may be developed into a lead compound for treating neuropathic pain.
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.
3UG3TR003149-02S1
Supplement to hiPSC-based DRG Tissue Mimics on Multi-well Microelectrode Arrays as a Tissue Chip Model of Acute and Chronic Nociception Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NCATS UNIVERSITY OF TEXAS DALLAS BLACK, BRYAN JAMES Dallas, TX 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

This study aims to determine whether a subset of understudied genes that are expressed in human and mouse dorsal root ganglia (DRG) tissues (critical for relaying the sensation of pain from the body to the central nervous system), are also expressed in human induced pluripotent stem cell DRG mimetics. The study will also determine if these genes are involved in neuronal excitability changes under inflammatory conditions and compare these responses to those of primary DRG neurons. Third and finally, the study will optimize genetic depletion of target genes enabling future fundamental and preclinical research studies.
3R01NS111929-01A1S1
Anatomic, Physiologic and Transcriptomic Mechanisms of Neuropathic Pain in Human DRG 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 DOUGHERTY, PATRICK M Houston, TX 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

Using neural tissues from pain patients, this project will investigate mechanisms of neuronal and/or immune dysfunction driving chronic pain. The researchers will use spatial transcriptomics on human dorsal root ganglion (DRG) and spinal cord tissues to examine the cellular expression profile for these targets using the 10X Genomics Visium technology. The use of tissues from control surgical patients and organ donors as well as surgical patients with neuropathic pain will enable validation of expression of these targets in human tissue as well as indication of their potential involvement in neuropathic pain. This collaborative effort will use DRGs removed from pain-phenotyped patients during neurological surgery, as well as lumbar DRGs and spinal cord from organ donors. This study will map the spatial transcriptomes at approximately single cell resolution in the human DRG and spinal cord.
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.
3R37DA020686-13S1
Role for Tas2Rs in opioid addiction Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NIDA ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI KENNY, PAUL J. New York, NY 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

Opioids and other addictive substances have powerful rewarding properties that drive the development of addiction. They also have aversive properties that motivate their avoidance and protect against addiction. This project will explore the role of Type 2 Taste Receptor proteins (Tas2Rs or T2Rs) in regulating the aversive properties of opioids, potentially establishing an entirely new class of receptors that can be targeted for the development of novel addiction therapeutics.
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.
1RF1AG068997-01
Subchondral Bone Cavities in Osteoarthritis Pain Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS JOHNS HOPKINS UNIVERSITY CAO, XU; GUAN, YUN 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:

A key marker of inflammation in Osteoarthritis (OA) is accompanied by significantly increased sensory innervation within the diseased joint. This study aims to validate the hypothesis that defective bone resorbing cells are responsible for the enlarged bone cavity, giving rise to the inflammatory marker causing further increases in levels sensory innervation and resulting in increased OA pain perception.
3R01NS113257-01S1
Isolation of GPR160 for biochemical analysis of the activation mechanism and development of a high throughput screening assay to identify small molecule inhibitors Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS SAINT LOUIS UNIVERSITY SALVEMINI, DANIELA Saint Louis, MO 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

Neuropathic pain conditions are difficult to treat, and novel non-narcotic analgesics are desperately needed. The G protein-coupled receptor 160 (GPR160) has emerged as a novel target for analgesic development, as GPR160 in the spinal cord may play a role in the transition from acute to chronic pain. Cocaine- and Amphetamine-Regulated transcript peptide (CARTp) was identified as a ligand for GPR160. Blocking endogenous CARTp signaling in the spinal cord attenuates neuropathic pain, whereas intrathecal injection of CARTp evokes painful hypersensitivity in rodents through GPR160-dependent extracellular signal-regulated kinase (ERK) and cyclic AMP response element-binding pathways (CREB). This project will isolate and biochemically characterize GPR160 and establish methods for biochemical characterization of GPR160 interaction with CARTp activator. Researchers will miniaturize and optimize biochemical assay and scale up protein production for future high throughput biochemical screening to identify potent inhibitors of GPR160 activation. These studies are critical for defining the molecular mechanism of CARTp/GPR160 interactions and initiating large-scale screens for new inhibitors to develop novel therapeutics.
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.
3R35NS105092-03S1
The biophysics of skin-neuron sensory tactile organs and their sensitivity to mechanical and chemical stress Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS STANFORD UNIVERSITY GOODMAN, MIRIAM B Palo Alto, CA 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

This project will establish a rapid research pipeline for linking plant-derived compounds to nociception (pain) and to G Protein-Coupled Receptors (GPCRs) and ion channels in the druggable human genome. As more than 80% of these membrane proteins are conserved in the C. elegans nematodes, the study will screen for compounds and genes affecting nociception as well as to identify novel ligand-receptor pairs using this model organism. The study will test which understudied GPCRs and ion channels are involved in nociception as well as attraction or repulsion behaviors. This research has the potential to reveal novel ligand-receptor pairs that could serve as new entry points for improved or alternative pain treatments.
3R01DE029187-01S2
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 NINDS UNIVERSITY OF TEXAS HLTH SCIENCE CENTER AKOPIAN, ARMEN N; RUPAREL, SHIVANI B; TUMANOV, ALEXEI V San Antonio, TX 2020
NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for PA-18-906 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-023
Summary:

Chronic orofacial pain during Temporomandibular Disorders (TMD) and oral cancer is a significant health problem with scarce non-opioid treatment options. This study aims to validate critical regulators of the balance between protective immunity and immunopathology during chronic inflammatory diseases?tumor necrosis factor alpha superfamily members, LIGHT (TNFSF14) and lymphotoxin-beta (LT?) and their receptors, LT?R and Herpes Virus Entry Mediator (HVEM)?as novel therapeutic targets. The study also seeks to determine whether inhibition of LIGHT and LT? signaling prevents the development and inhibits maintenance of chronic TMD and oral cancer pain via peripheral mechanisms involving plasticity of immune, muscle and tumor cells as well as sensory neurons. The study will define the contribution of LIGHT and LT? signaling to TMD-induced excitability of trigeminal sensory neurons innervating the masseter muscle and joint. New validated therapeutic targets for prevention and treatment of orofacial pain that can be peripherally targeted would reduce side effects of current pain medicates related to drug dependence or tolerance.
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.
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.
3R01AR064251-07S1
Osteoarthritis Progression And Sensory Pathway Alterations Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NIAMS RUSH UNIVERSITY MEDICAL CENTER MALFAIT, ANNE-MARIE Chicago, IL 2020
NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

There is an urgent need for new non-opioid therapeutic agents that treat the pain associated with Osteoarthritis (OA) ? a chronic, progressive disease that leads to pain in weightbearing joints, pain during movement, and pain at rest. This project will refine techniques for targeting several proteins expressed in sensory neurons associated with OA pain, with the goal of testing the potential of these proteins to serve as targets for development of effective, non-opioid painkillers.
5R01DE027454-02
Modeling temporomandibular joint disorders pain: role of transient receptor potential ion channels Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NIDCR Duke University Chen, Yong Durham, NC 2019
NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073
Summary:

Masticatory and spontaneous pain associated with temporomandibular joint disorders (TMJD) is a significant contributor to orofacial pain, and current treatments for TMJD pain are unsatisfactory. Pain-related transient receptor potential (TRP) channels, expressed by trigeminal ganglion (TG) sensory neurons, have been implicated in both acute and chronic pain and represent possible targets for anti-pain strategies. Using bite force metrics, we found TMJ inflammation-induced masticatory pain to be significantly, but not fully, reversed in Trpv4 knockout mice, suggesting the residual pain might be mediated by other pain-TRPs. Our gene expression studies demonstrated that TRPV1 and TRPA1 were up-regulated in the TG in response to TMJ inflammation in a Trpv4-dependent manner. We hypothesize that TRPV1 and TRPA1, like TRPV4, contribute to TMJ pain. Our specific aims will examine the contribution of TRPV1, TRPV4, and TRPA1 to pathogenesis of TMJD pathologic pain including assessment of the role of neurogenic inflammation.
5R01NS104295-03
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.
3R01NS094461-04S2
TARGETING SPECIFIC INTERACTIONS BETWEEN A-KINASE ANCHORING PROTEINS (AKAPS) AND ION CHANNELS WITH CELL-PERMEANT PEPTIDES AS A NOVEL MODE OF THERAPEUTIC INTERVENTION AGAINST PAIN DISORDERS 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 SCIENCE CENTER SHAPIRO, MARK S SAN ANTONIO, TX 2019
NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

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