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 goal of the Pan lab is to leverage primary cell culture, neuromodulatory approaches, genetically engineered mice, and patient-derived xenograft models to provide insights into the prediction, prevention, and treatment of nervous system cancer and neurological disorders, with an initial focus on neurofibromatosis type 1 (NF1).
Neuron-cancer crosstalk in nervous system tumors
• Recent findings have demonstrated the critical role of neurons in cancer initiation and progression, and contributed to the emerging field of Cancer Neuroscience.
• NF1, a cancer predisposition syndrome, is a valuable platform to understand the interaction between neurons and neoplastic cells.
• Children with NF1 are born with mutations in the NF1 tumor suppressor gene and are predisposed to nervous system neoplasms (e.g., optic pathway gliomas [OPG] and malignant peripheral nerve sheath tumors [MPNST]).
• Using a genetically engineered mouse model (GEMM) of NF1-OPG, we uncovered that neuronal activity synergizes with the germline Nf1 mutation to drive the initiation of NF1-OPG (Pan et al., Nature, 2021, Figure 1-2).
• Using a variety of GEMM of NF1, we aim to determine the cellular and molecular mechanisms underlying the neuronal activity-mediated nervous system neoplasms associated with NF1.
Neuron-glia interactions and cognitive function
• In NF1, the germline NF1 mutation affects every cell type including neurons and glial cells. Our ongoing studies suggest that Nf1 mutations lead to dysregulated neuron-glia interactions and cognitive deficits, which could be exacerbated by chemotherapy.
• Using neuroscience approaches and GEMM of NF1, we aim to determine how Nf1 mutations lead to deficits in neuron-glial interactions and neurological function, and whether chemotherapy exacerbates the deficits (Figure 3).
Figure 1. Dark-rearing during a critical period inhibits optic glioma initiation. wild-type (WT, Nf1fl/fl) and Nf1 optic glioma (OG, Nf1fl/-;Gfap-Cre) mice raised in normal light/dark cycles (1st and 2nd groups), or reared in dark from 6-12 weeks of age (3rd group), when optic glioma typically initiates. These mice were analyzed at 24 weeks of age. Quantification of optic nerve volume and proliferation (%Ki67+ cells) reveals no tumor formation in the dark-reared OG group (OG-dark). *, p<0.05; **, p<0.01; ns, not significant.
Figure 2. Neuronal activity synergizes with the Nf1 mutation to drive the initiation and maintenance of Nf1-OPG.
Figure 3. Nf1 mutations and chemotherapy in neuron-glial interactions and neurological function.
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