Research
The Grace Lab aims to understand the neuroimmune mechanisms of chronic pain and its control. We are investigating the adaptive immune mechanisms that initiate and maintain neuropathic pain after traumatic nerve injury and delineating the analgesic mechanisms and therapeutic potential of the "master regulator" of the antioxidant response Nrf2.
The Role of B Lymphocytes in Regulating Neuropathic Pain
Funding: The US National Institutes of Health, grant R01 NS126252 (2022-2027; PIs: Grace, Heijnen); and the US Department of Defense, grants PR231301 (2024-2028; PIs: Grace, Heijnen) and PR180594 (2019-2024; PI: Grace)
A plethora of immune and glial cells play fundamental roles in the pathogenesis of neuropathic pain. Our research is showing that B cells, adaptive immune cells responsible for antibody production, have an important yet underappreciated role in initiating neuropathic pain.
In the context of nerve injury, the goals of this research program are to understand:
- The mechanisms by which B cells ultimately increase activity of neurons in pain pathways
- The signals that coordinate B-cell differentiation
- Where differentiated B cells reside
Exploiting the Antioxidant Master Regulator Nrf2 to Treat Neurological Disorders
Funding: The US National Institutes of Health, grants 1RF1NS113840 (2019-2024; PI: Grace) and UG3 NS127251-01A1 (2022-2024; PIs: Abell, Grace); and the Kleberg Foundation (2024-2026; PIs: Grace, Hu, Pan)
Oxidative stress, a central and unifying feature of many diseases, imposes tremendous societal burden—including neurological disorders. Drug discovery for diseases of oxidative stress has recently been reinvigorated, in part through an increased appreciation of the homeostatic role of the antioxidant nuclear factor Nrf2.
Activating Nrf2 drives the transcription of a suite of endogenous antioxidants, based on the local needs of the tissue, to resolve oxidative stress. Pharmacological activation of Nrf2 is a complete departure from previous attempts to resolve oxidative stress by supplementing antioxidants, which attempts have been unsuccessful in the clinic.
Our program is:
- Exploring the utility of Nrf2 activators for treatment of neuropathic pain, chemotherapy-induced cognitive impairment, and postoperative cognitive decline
- Identifying the mechanisms by which Nrf2 activators restore healthy neurological function
- Discovering and developing prodrug Nrf2 activators, which can be activated at sites of pathology, with few side-effects
HDAC6 Inhibitors as Potential Therapeutics for Chemotherapy-Induced Neuropathy
Funding: The US National Institutes of Health, grant R01 CA227064 (2022-2025; PIs Grace, Shepherd)
Chemotherapy-induced peripheral neuropathy is a major side effect of cancer treatment that frequently persists long into survivorship. Although no drugs have been approved by the US Food and Drug Administration to prevent or adequately manage this condition, histone deacetylase 6 (HDAC6) inhibitors are exciting potential candidates.
Previous work has shown that HDAC6 inhibition fully reverses established chemotherapy-induced peripheral neuropathy in cisplatin-treated mice. Ongoing work is aimed at delineating the non-epigenetic mechanisms by which these inhibitors persistently reverse chemotherapy-induced neuropathy.