Funded Projects

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R21 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-042
Summary:

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

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:

Chronic pain severely reduces the quality of life and ability to work for millions of Americans. Because misuse of opioids for chronic pain treatment contributes to opioid addiction and opioid overdose, there is an urgent need to study novel non-opioid mechanisms, targets, and treatment strategies for chronic pain. Many ion channels control the flow of electrical signals in peripheral sensory neurons and are thus key targets for understanding and treating chronic pain. This project will conduct detailed studies to identify major ion channel-related molecular activities, targets, and treatment strategies for chronic pain. In particular, this research will explore the role of a specific ion channel (lysosomal mechanosensitive ion channel, orTmem63A) in neuropathic pain resulting from nerve injury.

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: RFA-TR-22-011
Summary:

There is an urgent need to find new ways to treat chronic pain through better targeting of underlying biological processes. Research shows that flexible synapses within the amygdala brain region play a role in the progression of pain from acute to chronic, but the details are not fully understood. The receptor glutamate delta 1 helps to form and maintain synapses in the amygdala in inflammatory and neuropathic pain. This project will study how the shape and characteristics of glutamate delta 1 affect pain conditions that involve the amygdala, toward informing future development of pain medications. 

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: RFA-TR-22-011
Summary:

Chronic pain results in long-term changes throughout the central nervous system. These include abnormal structure and function of the frontal cortex region of the brain, which relays pain messages and also the common pain-related conditions depression, anxiety, and cognitive impairment. Peripheral nerve injury results in widespread and long-lasting changes to DNA in the frontal cortex. DNA methylation, in which chemical tags are attached to DNA, is one way the body controls the activity of genes over time. This control occurs via proteins that recognize tagged DNA, and some of these proteins do not work properly in the frontal cortex many months after nerve injury. These changes occur after nerve injury and are linked to mechanical sensitivity. This project will determine this DNA-binding protein is a good target for finding new medications for chronic pain. 

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.

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:

Migraine is a painful and debilitating neurological condition, the development and maintenance of which involves the neuropeptide calcitonin gene-related peptide (CGRP). An exciting development in the treatment of migraine is the recent FDA approval of a new class of CGRP-targeted therapies designed to prevent migraine. However, these drugs meet a clinically relevant endpoint for only about half of the patients. This project will test the hypothesis that the high-affinity CGRP receptor AMY1 is a novel and unexplored target that mediates specific migraine-related behaviors in the brain and/or periphery to cause migraine. Validation of CGRP and AMY1 receptor involvement in migraines will create a new direction for the development of novel drugs and provide alternatives to opioids for management of migraine and potentially for other chronic pain conditions.

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:

Identification of new targets and mechanisms underlying chronic neuropathic pain is essential for the discovery of novel treatments and preventative tactics for better neuropathic pain management. A recent exploration of next-generation RNA sequencing identified a large, native, full-length long noncoding RNA (lncRNA) in mouse and human dorsal root ganglion (DRG). It was named as nerve injury-specific lncRNA (NIS-lncRNA), since its expression was found increased in injured DRGs, in response to peripheral nerve injury, but not in response to inflammation. Preliminary findings revealed that blocking the nerve injury-induced increases in DRG NIS-lncRNA levels ameliorated neuropathic pain. This project will validate NIS-lncRNA as a therapeutic target in animal models of neuropathic pain and in cell-based functional assays utilizing human DRG neurons. Completion of this proposal will advance neuropathic pain management and might provide a novel, non-opioid pain therapeutic target.

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:

Dorsal root ganglion (DRG) neuronal hyperexcitability is central to the pathology of neuropathic pain and is a target for local anesthetics, even though the efficacy of local anesthetic patches has been mixed. The coordinated movement of ion channels, especially voltage-dependent sodium channels, from intracellular pools to the sites of nerve injury has been suggested to be an underlying cause of electrogenesis and ectopic firing in neuropathic pain conditions. Recent studies identified Magi1 as a scaffold protein responsible for sodium channel targeting and membrane stabilization in DRG neurons. This project will determine whether reducing the expression Magi1 could disrupt intracellular trafficking of sodium channels in DRG neurons under neuropathic injury conditions, and could therefore serve as a potential therapeutic target for neuropathic pain.

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:

Immune checkpoint proteins regulate the immune system to prevent it from indiscriminately attacking cells. Some cancers activate these immune checkpoints to avoid attack, and drugs that target certain immune checkpoints are approved for cancer treatment. The same pathway may also be involved in pain because immune checkpoint proteins, such as programmed death 1 (PD-1) and the molecule that binds to it (programmed death ligand 1 [PD-L1]), also are found in sensory neurons, microglia, and macrophages. This project will investigate PD-1/PD-L1 in different cell populations to determine their contribution to pain and to the effects of opioids such as morphine. This knowledge may help identify new drugs for pain management that modify immune checkpoint activity.

NOFO Title: HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes and Cells (U19 Clinical Trial Not Allowed)
NOFO Number: NS22-018
Summary:

This project will use a variety of state-of-the-art technologies to generate a comprehensive  gene expression map of human peripheral nerves. The research will enhance understanding about genes involved in various painful conditions associated with nerve damage (neuropathies) resulting from injury or disease. This research will analyze DNA sequences of individual neuronal and non-neuronal cells in human nerve cells (from individuals with and without pain located outside the spinal cord that are involved in pain signal transmission. The findings, together with other imaging and computational approaches, will be used to generate a spatial atlas of the human dorsal root ganglia – a key hub for pain communication between the brain and spinal cord.

NOFO Title: HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes and Cells (U19 Clinical Trial Not Allowed)
NOFO Number: NS22-018
Summary:

This project will identify molecular characteristics of human sensory neurons and non-neuronal cells from the human dorsal root ganglia. This structure located outside the spinal cord is integrally involved in communicating pain signals to and from the brain. The research will use molecular approaches to characterize tissues obtained from organ donors and in patients who experience chronic pain. The findings will also help generate a connectivity map, or “connectome,” of nerve cell connections between the dorsal root ganglia of the spinal cord and the brain.

NOFO Title: HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes & Cells (U19 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-22-018
Summary:

Migraine is one of the most common primary headache disorders and affects one in four U.S. households; however, there are few effective treatments. Migraine is a complex neurological disorder mediated in part by alterations in the way the brain processes sensations like touch and pain (somatosensation) in the head. These sensations are transmitted by the trigeminal nerve and a cell cluster called the trigeminal ganglion. To better understand the function of the human trigeminal system and its role in migraine, this project will conduct multiple types of molecular analyses of human trigeminal ganglia from people with and without migraine. The project will also perform sensory evaluations and measure the signals sent from the trigeminal ganglion to the brain in individuals with and without migraine.

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.