Stroke is the primary cause of long-term disability. However, no effective treatment is available for the majority of stroke patients. Interestingly, a process of self-repair and recovery starts to occur days following stroke. Mounting evidence suggests that axonal plasticity is a critical aspect of this process, as it is essential for establishing new neural connections to compensate for the stroke-induced functional loss. However, after injury, this regrowth and remodeling in the adult mammalian central nervous system (CNS) is limited. The weak intrinsic growth capacity in neurons and the inhibitory factors from extrinsic glial environments are among the major causes that limit regeneration. This potential for regrowth has emerged as an alternative and potentially more tractable target in stroke research. Indeed, emerging data suggest that Ras-related C3 botulinum toxin substrate 1 (Rac1), a Rho GTPase, plays a central role in axonal regeneration in the injured brain, specifically by stimulating neuronal intrinsic growth and counteracting the growth inhibitory signaling that leads to growth cone collapse. The overall goal of this proposal is to define the functional role of Rac1 in neurite regeneration after stroke and uncover its underlying neuronal and astrocytic specific mechanisms. We showed that pharmacological inhibition of Rac1, starting one week after stroke, results in decreased functional recovery as well as reduced axonal density while post-stroke over-expression of Rac1 improves brain functional recovery. Furthermore, Rac1 inhibition decreases activation of intrinsic pro-regenerative molecules in mice after stroke and reduced axonal density in neuronal culture following oxygen-glucose deprivation. In contrast, inhibition of Rac1 increases glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycan (CSPG), both of which are major astrocytic inhibitory signals after ischemia. Finally, aging leads to a decline in the levels/activities of proteins involved in the Rac1 pathway in the brain, and we aim to test if activating this pathway in young and aging brains could enhance neurite regeneration and improve post-stroke functional recovery. We will use a combination of pharmacological tools, diffusion tensor imaging, inducible knockout mice and viral transduction systems to over-expression Rac1 in vivo. These studies represent the first steps in understanding the endogenous pathways that promote brain axonal regeneration and subsequently recovery following stroke.
Stroke is the most common cause of disability. We have recently found that Rac1 signaling is an important contributor to the regeneration of neuronal projections by stimulating neuronal growth potential and reducing astrocytic growth inhibition. In this application, we will pursue a focused investigation on the functional role of this signaling pathway in stroke in an attempt to develop novel treatments for stroke.
| Liu, Lin; Yuan, Hui; Yi, Yanhua et al. (2018) Ras-Related C3 Botulinum Toxin Substrate 1 Promotes Axonal Regeneration after Stroke in Mice. Transl Stroke Res 9:506-514 |
