Funded Projects

Cholecystokinin B receptor (CCKBR) is a molecule found in the brain that helps regulate anxiety and depression but also influences the development of tolerance to opioids. CCKBR levels are also increased in models of nerve injury-induced (neuropathic) pain. Therefore, targeting CCKBR may offer a new approach to treating neuropathic pain and the associated anxiety and depression. Researchers have developed mouse antibodies that can inactivate CCKBR. However, to be usable in humans without causing an immune response, these antibodies need to be modified to include more human sequences. This project will use a fragment of the CCKBR antibody, modify it with the addition of human antibody sequences, and then select the clones that bind most strongly and specifically to human CCKBR. These will then be tested in cell and animal models of neuropathic pain to identify the most promising candidates for further evaluation in humans.

This International Cooperative Biodiversity Group application aims to discover and develop small molecule drug leads from cultured marine microbes and diverse coral reef organisms collected from Fiji and the Solomon Islands. Drug discovery efforts will focus on four major disease areas of relevance to the United States and low- and middle-income countries: infectious disease, including tuberculosis and drug-resistant pathogens; neglected tropical diseases, including hookworms and roundworms; cancer; and neurodegenerative and central nervous system disorders. Screening in these therapeutic areas will be performed in collaboration with two major pharmaceutical companies, two highly respected academic groups, and various testing centers and government resources that are available to facilitate drug discovery and development. The acquisition of source material for this program will be linked to biotic surveys, informed by ecological investigations addressing the chemical mediation of biotic interactions, and enriched using ecology-based strategies designed to maximize secondary metabolite production and detection.

MNK-eIF4E signaling is activated in nociceptors upon exposure to pain or peripheral nerve injury, promoting cytokines and growth factors and increasing nociceptor excitability, which leads to neuropathic pain. Genetic or pharmacological inhibition of MNK signaling blocks and reverses nociceptor hyperexcitability as well as behavioral signs of neuropathic pain. A clinical phase drug for cancer shows strong specificity as an MNK inhibitor but requires optimization because MNK inhibition in the central nervous system (CNS) may lead to depression, an unacceptable side effect for a neuropathic pain drug. The research team plans a targeted medicinal chemistry and screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment with the goal of restricting its CNS penetration while retaining potency, specificity, and in vivo bioavailability and efficacy.

Neuropathic pain is a debilitating and complex medical condition for which safe and non-addictive treatment options are urgently needed. This project aims to develop new strategies for treating neuropathic pain by controlling the activity of transmembrane protein 97 (TMEM97), also known as the sigma 2 receptor, which has been shown to relieve pain in an animal model of neuropathic pain. The research aims to develop a new molecule that increases TMEM97 activity and is safe for human use, toward obtaining approval from the U.S. Food and Drug Administration for Phase I clinical testing. 

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

An important component of neuropathic pain is spontaneous or ongoing pain, such as burning pain or intermittent paroxysms of sharp and shooting pain, which may result from abnormal spontaneous activity in sensory nerves. However, due to technical limitations, spontaneous activity in sensory neurons in vivo has not been well studied. Using in vivo imaging in genetically-modified mice, preliminary findings identified spontaneously-firing clusters of neurons formed within the dorsal root ganglia (DRG) after traumatic nerve injury that exhibits increased spontaneous pain behaviors. Furthermore, preliminary evidence has been collected that cluster firing may be related to abnormal sympathetic sprouting in the sensory ganglia. This project will test the hypothesis that cluster firing is triggered by abnormal sympathetic inputs to sensory neurons, and that it underpins spontaneous paroxysmal pain in neuropathic pain models. Findings from this project will identify potential novel therapeutic targets for the treatment of neuropathic pain.

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.

Activation of immune cells (microglia) in the central nervous system and neuroinflammation have emerged as key drivers of neuropathic pain. These processes can be triggered by release of ATP, the compound that provides energy to many biochemical reactions. The source and mechanism of ATP release are poorly understood but could be targets of novel treatment approaches for neuropathic pain. This project will use genetic, pharmacological, and electrophysiological approaches to determine whether a large pore channel called Swell 1 that spans the cell membrane is the source of ATP release and resulting neuropathic pain and thus could be a treatment target.

Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system; however, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. An intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. The goal of this study is to develop a CNS-penetrant small-molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions.

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.

Neuropathic corneal pain (NCP) causes patients to have severe discomfort and a compromised quality of life (QoL). The lack of signs observed by standard examination has resulted in misdiagnosis as dry eye disease (DED). An optical biopsy using laser in vivo confocal microscopy (IVCM) revealed that microneuromas (bulbs at the ends of severed nerves caused by buildup of molecular constituents) are present in NCP but not DED and may serve as a biomarker for NCP. The aims are to (1) use a database of more than 2,000 DED/NCP subjects and more than 500,000 IVCM images to confirm that the presence of microneuromas is an appropriate biomarker for NCP, (2) provide biological validation of microneuromas, (3) develop a validated artificial intelligence (AI) program for automated identification of microneuromas, and (4) establish the clinical utility of microneuromas observed by IVCM as a biomarker for NCP in a prospective, multicenter study.

An International Cooperative Biodiversity Group with an interdisciplinary leadership team of physicians, pharmacologists, evolutionary biologists, and chemists will discover and develop therapeutic agents produced by Brazilian symbiotic bacteria. The team will target three therapeutic areas: 1) infectious fungal pathogens, 2) Chagas disease and leishmaniasis, and 3) cancers of the blood. All three areas represent major threats to human health that need to be addressed with new therapeutic agents. Internationally, invasive fungal diseases kill more people than malaria or TB, while Chagas disease imposes a special burden on Brazil, killing as many Brazilians as TB. Leishmaniasis has now passed Chagas disease in the Brazilian population. Despite major improvements in cancer chemotherapy, cancer is projected to result in 8 million deaths internationally this year (13% of all deaths, WHO) and an estimated 13 million per year by 2030.

Recent studies have reported that neuropathic pain involves changes in the central nervous system that are linked to necroptosis (programmed necrotic cell death) and release of cellular components that create neuroinflammation. Necroptosis is a type of necrotic cell death affected by the protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1 or RIP1). Preliminary studies also indicate that pain increases levels of RIPK1 in key brain regions implicated in pain processing. This project aims to further validate RIPK1 as a target for neuropathic pain using a newly developed positron emission tomography imaging approach. The work will pave the way for new brain-penetrant RIPK1 inhibitors as a safe, effective, and nonaddictive treatment approach for neuropathic pain.