Ischemic stroke is now the most frequent cause of persistent neurologic disability in the US. Despite considerable effort there are no therapies that can reduce injury or restore function once a stroke occurs. Over the past several years, our view of stroke as a "neuronal disease" has been transformed into the concept of stroke as a "neurovascular" disease, and more recently into the novel theory that stroke is truly a "systemic" disease in which peripheral inflammatory processes play a fundamental role. This peripheral immune response is a target for stroke therapy, as reducing peripheral infiltration of circulating leukocytes, specifically monocytes and neutrophils, decreases ischemic injury. Transforming growth factor ? activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family has been recently recognized as an indispensible signaling molecule in the innate immune response to brain injury. The proposed work will examine the effects of loss of TAK signaling on post-stroke inflammation using selective deletion of TAK in myeloid cells. Mechanistic studies will be performed in TAK1 knockout animals (Aim 1). We will then determine the neuroprotective efficacy of pharmacologically inhibiting TAK in aged mice, a clinically relevant animal model for stroke (Aim 2). These exploratory studies will hopefully identify new biological targets for therapeutic intervention for patients with stroke.
There is considerable evidence from both clinical and experimental studies that the outcomes after stroke differ in the aged. Experimental studies need to test promising therapies in a variety of animal models before attempting to move them into clinical trials. New data from the bench has identified a novel signaling pathway involved in the response to stroke (TAK-1) and we will test if inhibition of this pathway is protective in agin and explore potential mechanisms for its protective actions using cell specific knockout models.
|Crapser, Joshua; Ritzel, Rodney; Verma, Rajkumar et al. (2016) Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. Aging (Albany NY) 8:1049-63|
|Venna, Venugopal Reddy; Benashski, Sharon E; Chauhan, Anjali et al. (2015) Inhibition of glycogen synthase kinase-3Î² enhances cognitive recovery after stroke: the role of TAK1. Learn Mem 22:336-43|