Click the red plus signs to see detailed information on research conducted in the Dantzer, Grace, Heijnen-Kavelaars and Shepherd Laboratories.
1. Test of 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
2. Test of the hypothesis that inflammation-induced depression is mediated by the negative impact of the metabolic requirements of neuroinflammation on brain energy metabolism
Tumor-associated wheel running decrement precedes inflammation in brain, liver, or serum.
- A: nightly wheel running time course in tumor bearing and control mice. Green line denotes first termination day (day 9), yellow line denotes second termination (day 16), and red line denotes final termination (day 27, n=6/group).
- B: average hourly wheel running in tumor bearing (red) and control (black) mice during days shown. Tumor bearing mice show a progressive loss in wheel running peak and duration throughout tumor growth.
- C: tumor volume, measured weekly, and,
- D: tumor weights from each group.
- E: Il1b expression time course in hippocampus.
- F: Il1b,
- G: Il6 and
- H: Tnf expression time course in liver.
- I: plasma IL-6 concentration. *, P<0.05, ***, P<0.001, 2-way ANOVA (A) or 1-way ANOVA (E, F, G, H, I) with post-hoc Bonferroni-corrected t-test.
(From Grossberg et al., Cancer Res, 2018, Fig. 3)
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.
- Tested using genetic and pharmacological approaches to modulate Nrf2 activity in mouse models of neuropathic pain.
- 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 Drs. 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 at understanding the contribution of non-neuronal cells to onset and resolution of pain and cognitive deficits and the potential of mesenchymal stem cell based intervention to promote resolution.
Mesenchymal stem cells to treat chemobrain
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.
In this project we test the hypothesis that cisplatin induces cognitive deficits by causing persistent mitochondrial damage leading to 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
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, MD Anderson, 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.
Role of the immune system in resolution of pain and co-morbid
(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.
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 obesity, which is 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 in obesity.
Image 4: The canonical renin-angiotensin system, and the enigmatic role of AT2R in chronic pain.