Stroke is among the leading causes of long-term disability in US. With declining mortality rates from stroke and lack of treatments to enhance neurological recovery, the socioeconomic burden of disability from stroke has been steadily rising. Brain repair involves multiple, temporally and spatially distinct mechanisms, Rho- associated kinase (ROCK) is a point of convergence for multiple deleterious signaling pathways impeding plasticity and recovery after injury. ROCK inhibitors prevent neurite retraction and promote axon regeneration, facilitate remyelination via oligodendrocyte proliferation, differentiation and maturation, and prevent acute inflammatory microglial activation. Indeed, Rho/ROCK inhibitors have already achieved many preclinical milestones to improve neurological outcome after spinal cord injury. The central hypothesis of this proposal is that therapeutic inhibition of ROCK enhances brain plasticity and remodeling and improve neurological outcome after stroke. In this highly translational project, we propose three aims to develop ROCK as a novel target in stroke recovery. Building on pilot data showing that delayed ROCK inhibition improves neurological outcome after stroke without reducing the infarct volume.
Aim 1 will identify the relevant ROCK isoform responsible for promoting stroke recovery (R0CK1 vs. R0CK2), and optimize the therapeutic paradigm. Clinically-relevant cortical or subcortical stroke models with functional endpoints, as well as novel in vitro models of ischemic neurite retraction will be used.
Aim 2 will then dissect the mechanisms of enhanced post-stroke recovery by ROCK inhibition using physiological and tissue surrogates of repair and plasticity. We will use cutting-edge optical imaging, MRI, and morphological tools, to investigate the impact of ROCK inhibition on neurovascular remodeling, including cortical activation, axonal sprouting and white matter connectivity, and neurogenesis and angiogenesis.
Aim 3 will then carry out critical studies to facilitate clinical translation by investigating whether common modifiers of stroke recovery such as age and comorbid states including diabetes and small vessel disease modulate the efficacy and safety of ROCK inhibition in stroke recovery.
This proposal will develop selective inhibitors of ROCK as a novel mode of therapy for stroke recovery for bedside testing. The information gained in these studies will likely have a broader impact on neurological recovery in other forms of brain injury as well, such as trauma and intracranial hemorrhage.
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