Stroke is the leading cause of long-term disability. However, the mechanisms underlying stroke recovery are not well understood, and there are few therapeutic approaches to promote stroke recovery. Recent studies suggest that the inflammatory response following cerebral ischemia could have both beneficial and detrimental effects. Therefore, investigating pathways that regulate inflammation may provide an opportunity for developing novel therapeutics in stroke recovery. Rho-kinase (ROCK) has been shown to be involved in vascular inflammatory disease and in stroke recovery. However, ROCK inhibitors, when given in vivo, cannot distinguish whether the benefits are due to inhibition of ROCK in vascular, inflammatory, and/or neuronal cells. Furthermore, pharmacological inhibitors of ROCK have nonspecific effects on other signaling pathways, and cannot distinguish the effects of the two ROCK isoforms, ROCK1 and ROCK2. Thus, a genetic approach using mutant mice with conditional deletion of ROCK isoforms offers the best strategy for understanding the contribution of the two ROCK isoforms in neuro-inflammation and stroke recovery. The central hypothesis is that ROCK1 and ROCK2 play different roles in stroke recovery following focal cerebral ischemia through their effects on inflammation.
In Specific Aim 1, the PIs will investigate the function of ROCK1 and ROCK2 in stroke recovery and inflammation. They will subject haplo-insufficent ROCK1+/- and ROCK2+/- mice to middle cerebral artery occlusion (MCAO) and will measure the motor and cognitive function, inflammation, angiogenesis, neurogenesis and apoptosis over 4 weeks. In addition, they will use ROCK1+/- and ROCK2+/- bone marrow transplanted mice to specifically investigate the role of ROCK in hematopoietic inflammatory cells in the stroke recovery.
In Specific Aim 2, the PIs will investigate the function of ROCK in T cell-mediated inflammation and stroke recovery. They will isolate T cells from CD4+T cells-specific ROCK1 and ROCK2 knockout mice (CD4Cre ROCK1flox/flox and CD4CreROCK2flox/flox) and investigate the role of ROCK1 and ROCK2 in regulation of T helper cell lineage differentiation in response to oxygen glucose deprivation. They will further test if ROCK1 and ROCK2 have differential role in regulating T cell mediated inflammatory response in vivo. Furthermore, they will use CD4CreROCK1flox/flox and CD4CreROCK2flox/flox mice to investigate the role of ROCK1 and ROCK2 in T cells in mediating post-stroke inflammation. This proposed study may increase our understanding of inflammation during stroke recovery and lead to identify a novel target to promote stroke recovery. This project is proposed as part of a career development plan to obtain training in gene manipulation and neuro-immunology. The candidate is an instructor in the Department of Physical Medicine and Rehabilitation at Harvard Medical School and is establishing herself as a new investigator with the long-term goal of investigating the mechanisms of stroke recovery. She has assembled a strong multidisciplinary mentoring team and the research will be conducted at the Brigham and Women's Hospital, which provides an excellent research environment and resources.
Stroke is the leading cause of long-term disability in the adult population. This proposal will help discover the mechanisms that mediate stroke recovery. The findings from the proposed studies may provide new targets for pharmacological intervention to promote stroke recovery.
|Li, Shanshan; Wang, Yao; Jiang, Ze et al. (2018) Impaired Cognitive Performance in Endothelial Nitric Oxide Synthase Knockout Mice After Ischemic Stroke: A Pilot Study. Am J Phys Med Rehabil 97:492-499|
|Wang, Qing Mei; Cui, Huashun; Han, Soo Jeong et al. (2014) Combination of transcranial direct current stimulation and methylphenidate in subacute stroke. Neurosci Lett 569:6-11|