Department of Neurosciences
Case Western Reserve University
School of Medicine
My laboratory has a long-standing interest in understanding how neurons develop and respond to tissue injury.
We found that activin A from skin has profound effects on sensory neuron differentiation, and more recently, learned that this same factor has a critical role in changing pain behaviors following inflammation. We originally discovered that the differentiation of primary sensory neurons is regulated by a skin-derived factor eventually identified as activin A (Ai et al., 1999; Hall et al., 2001; Hall et al., 2002). In addition to the role in development, we found that after local inflammation, activin A increases in skin and produces an acute increase in pain behaviors resulting from interactions with ion channels and a prolonged effect due to the increase in CGRP containing neurons that mediate swelling and alter pain responses (Cruise et al., 2004; Xu et al., 2005). We have shown that Activin A and NGF have synergistic effects on sensory neuropeptide expression and signal through separate receptors and independent intracellular signals (Xu and Hall, 2007). Further, Activin A injection reduces paw withdrawal thresholds in response to mechanical stimulation as well as heat stimuli, demonstrating that activin increases pain behaviors within minutes, and with our collaborators we have shown that Activin A sensitizes the capsaicin receptor TRPV1, and thermal hyperalgesia after activin is reduced in TRPV1 null animals (Zhu et al.,2007). These exciting discoveries place activin A in a central role in pain regulation after inflammation.
In a second project, we have shown that activin is rapidly increased after focal cerebral ischemia or “stroke” and that activin appears to function as a paracrine agent in neuroprotection after oxidative stress (Mukerji et al., 2007). The role of hypoxia inducible factor in activin induction will be studied using genetic deletion models in transgenic mice. Pilot data suggest that activin A administration spares neurons in vivo and current studies explore its action in mouse stroke models, and exciting new data suggest that we can use the small animal imaging core to capture information about this stroke benefit in our mouse models. We are interested in ways to provide that benefit therapeutically.