Click the red plus signs to see detailed information on research conducted in the Dantzer, Grace, Heijnen-Kavelaars and Shepherd Laboratories.
The Dantzer Lab's work includes:
- Testing the hypothesis that cancer-related fatigue emerges from a competition between the energy requirements of physical exercise and those of the tumor, with this situation being exacerbated by mitochondrial dysfunction induced by cancer therapy
- Preclinical studies of the mechanisms of inflammation-induced sickness and depression-like behavior
The metabolic basis of cancer-related fatigue (R01CA193522)
Funded by the National Institute of Health, National Cancer Institute
Proposed model for cancer-associated fatigue. In response to the energy demand of physical exercise, the liver maintains blood glucose levels by suppressing glucose import and glycolysis and favoring gluconeogenesis. Lactate, produced by exercising muscles, is converted to glucose via the Cori cycle, thereby providing fuel for further skeletal muscle utilization (left). In tumor-bearing mice (right), this adaptive response is suppressed as the tumor captures the Cori cycle for its own needs. This leads to decreased glucose availability and accumulation of lactate in the skeletal muscles, limiting further exertion (adapted from Grossberg et al., Brain Behav Immun, 2020).
Chronic pain afflicts ~100 million Americans, and the current therapies - that target only neurons - are minimally effective.
The goal of the Grace Lab is to understand the neuroinflammatory mechanisms that drive chronic pain so that new treatment strategies can be developed.
The antioxidant transcription factor Nrf2: a new therapeutic target for neuropathic pain
Funded by NIH Grant 1RF1NS113840
- In rodent models of pain, reactive oxygen and nitrogen species are elevated in neuronal, immune and glial cells in the dorsal root ganglia and spinal cord dorsal horn.
- Reactive oxygen and nitrogen species promote hyperexcitability of neurons in pain pathways via several mechanisms (summarized in Fig. 1), including:
- Direct activation of nociceptors via transient receptor potential (TRP) channels.
- Impairing mitochondrial function, which is believed to contribute to the spontaneous activity of nociceptors.
- Activation signaling cascades that produce proinflammatory mediators that increase excitability of neurons in the pain neuraxis.
- This project tests whether activation of the antioxidant transcription factor Nrf2 will restore redox balance to simultaneously resolve multiple mechanisms that have been implicated in driving neuropathic pain.
- Tested using genetic and pharmacological approaches to modulate Nrf2 activity in mouse models of neuropathic pain.
- A range of biochemistry, microscopy and live-cell imaging techniques are used to investigate the molecular and cellular consequence of Nrf2 activation in mouse and human tissues.
- The insights gained from these investigations may lead to novel therapeutics for mechanism-based treatment of pain.
Fc Gamma Receptor Signaling: A New Pathway for Sustained Neuropathic Pain
Funded by the Rita Allen Foundation and Department of Defense Grant W81XWH19-1-0160
- Spinal cord glia are activated after peripheral nerve injury, and release proinflammatory mediators that promote hyperexcitability of neurons in pain pathways.
- Although the signals that trigger microglial reactivity after peripheral nerve injury have been closely studied, those that maintain astrocyte reactivity and prevent pain resolution are not well understood.
- We have evidence to suggest that sustained mediator production by astrocytes is facilitated by activation of FcgR subtype IIa (FcγRIIa) via autoimmune complexes. These receptors are uniquely expressed by astrocytes after peripheral nerve injury (Fig. 2).
- This project aims to delineate the mechanisms of FcgRIIa signaling after peripheral nerve injury, and to identify the autoantigens involved.
The studies led by Annemieke Kavelaars (@akavel) and Cobi J. Heijnen (@CobiHeijnen) aim to understand the neurotoxic mechanisms underlying cancer treatment induced cognitive impairment, neuropathic pain and accelerated aging with the aim to identify novel curative and preventive interventions.
We also aim to understand the contribution of the immune system to the onset and resolution of pain and cognitive deficits. Another focus of research is the potential of mesenchymal stem cell based interventions including exosomes and isolated mitochondria to promote resolution of neurotoxicities.
Mesenchymal stem cells to treat chemobrain
Funded by NIH RO1 CA208371
Chemotherapy-induced cognitive deficit (“chemobrain”) is a major side effect of cancer treatment that frequently persists long into survivorship. There are no FDA-approved drugs for prevention or treatment of chemobrain, and the underlying mechanisms are poorly understood.
We test the hypothesis that cisplatin induces cognitive deficits by causing persistent mitochondrial damage leading to neuronal stem cell depletion, abnormalities in white matter organization and dendritic spine integrity, and impaired connectivity. We propose that nasally administered MSC reverse all these aspect of chemobrain by restoring mitochondrial function in the brain.
A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity
Funded by NIH RO1 CA230531
Cognitive impairment (chemobrain) is a common neurotoxicity associated with chemotherapy treatment that affects an estimated >50% of patients. We identify the A3 adenosine receptor subtype (A3AR) as a novel target for therapeutic intervention.
In this collaborative project led by Drs. Salvemini (St. Louis University) and Heijnen, we test the hypothesis that chemotherapy dysregulates adenosine homeostasis and signaling at A3ARs by disrupting the function of ectonucleotidases and ADK, leading to neuroinflammation and mitochondrial dysfunction that culminate in behavioral toxicities; A3AR agonists by interrupting these processes provide an effective new approach in CICI.
Chart showing the roe of the immune system in resolution of pain and co-morbid depression
Role of the immune system in resolution of pain and co-morbid depression
Funded by NIH RO1 NS073939
Transient pain and depressed mood commonly develop in response to tissue damage and inflammation, resulting in behavioral responses such as reduced activity, guarding of damaged tissue and social withdrawal. These behavioral changes serve an adaptive purpose and should resolve after tissues heal and inflammation resolves. Resolution may result from dissipation of the driving signals or require active specific regulatory pathways. We propose that the resolution of depression and pain depends on an active regulatory process involving endogenous resolution pathways; dysregulation of these resolution processes results in transition into maladaptive depression and chronic pain.
In this project, we use mouse models to test the overall hypothesis that CD8 T cells promote resolution of depression and pain by inducing IL-10 production by monocytes/macrophages. This leads to the downregulation of glial activation in the central nervous system. In addition, we propose that CD8 T cells that have been educated in vivo in either an antigen-specific or a non–antigen-specific way will be more efficient than T cells from naïve mice will be in promoting resolution of inflammation-induced pain and depression.
Targeting HDAC6 to prevent and treat chemotherapy-induced neuropathy and cognitive impairment
Funded by NIH RO1 CA227064
Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment (CICI) are major side effects of cancer treatment that frequently persist long into survivorship. No drugs have been approved by the US Food and Drug Administration to prevent and/or adequately manage CIPN and CICI. This application aims at filling this void. A concern when designing drugs to manage CIPN and CICI is that they should not impair tumor control. Ideally, agents to control these neurotoxicities should also enhance tumor control. Recent findings indicate that inhibitors of histone deacetylase 6 (HDAC6) meet these goals.
In this project we test the hypothesis that HDAC6 inhibition prevents and reverses CIPN and CICI in mice with or without tumors by targeting mitochondrial health, oxidative stress and downstream neuroimmune pathways.
Validation of fibroblast-derived PI16 as a novel target for pain treatment
Funded via the HEAL initiative NIH grant R01NS116704
Chronic pain and the addictive effects of opioids used to control pain are major health problems affecting millions of Americans. Validation of novel targets for the safe treatment of chronic pain is urgently needed. We identified peptidase inhibitor 16 (PI16) as a novel regulator of chronic pain in an unbiased RNA seq screen (Singhmar et al.). PI16 is a putative peptidase inhibitor that has not been studied in the context of pain. We showed that male and female Pi16-/- mice are protected against mechanical allodynia in the spared nerve injury (SNI) and paclitaxel models of neuropathic pain. Along the neuraxis, 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.
The overall objective of this project is to validate PI16 as a novel target for the treatment of chronic pain using mouse models and human tissues of neuropathy patients and controls and to identify the underlying mechanisms. Our central hypothesis is that increased PI16 secretion by DRG meningeal and perineurial fibroblasts promotes chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG. The significance is in the validation of PI16 as a novel, potentially druggable, regulator of chronic pain and the discovery of fibroblasts as key regulators of chronic pain.
We collaborate with Ted Price at UT Dallas and Erobo Ubogu at University of Alabama in Birmingham.
Tumor-immune Interactions in Chemotherapy-Induced Peripheral Neuropathy (CIPN)
- CIPN is associated with chronic, debilitating pain hypersensitivities extending many months after treatment.
- It is well-established that chemotherapy exerts directly toxic effects on neurons, but there is also a growing appreciation for the role of the immune system in generating, maintaining and resolving this pain.
- Using rodent models of cancer and CIPN, we aim to determine the extent to which cancer alters the status of the immune system, and the knock-on effects this has on the development of CIPN.
Image 1 and 2: In neuropathic pain states, loss of intraepidermal nerve fiber density (PGP9.5; green) is associated with elevated density of macrophage-related markers (Iba1; red).
Image 3: Schematic illustrating the neuroimmune crosstalk in
neuropathic pain triggered by Ang II.
Angiotensin Receptor Signaling and Neuro-Immune Crosstalk in Musculoskeletal Pain
- Angiotensin II (Ang II) is traditionally known for mediating vasoconstriction and influencing blood pressure, but recent studies have implicated Ang II signaling in chronic pain states.
- Circulating levels of Ang II are also elevated in chronic inflammation, obesity and diabetes, all of which are associated with an increased risk of developing chronic pain.
- Using rodent models of musculoskeletal pain, we are investigating the effect of Ang II signaling on immune system activity, and the extent to which this underlies chronic pain severity and risk.
Image 4: The canonical renin-angiotensin system, and the enigmatic role of AT2R in chronic pain.
Image 5: Conditions where Ang II is elevated aggravate multiple disease states associated with pain, in this instance, osteoarthritis