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 mulfiple, temporally and spafially disfinct mechanisms, Rho- associated kinase (ROCK) is a point of convergence for mulfiple 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 therapeufic inhibition of ROCK enhances brain plasficity and remodeling and improve neurological outcome after stroke. In this highly translafional 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 funcfional endpoints, as well as novel in vitro models of ischemic neurite retracfion will be used.
Aim 2 will then dissect the mechanisms of enhanced post-stroke recovery by ROCK inhibition using physiological and fissue surrogates of repair and plasficity. We will use cutting-edge opfical imaging, MRI, and morphological tools, to invesfigate the impact of ROCK inhibifion on neurovascular remodeling, including cortical activafion, axonal sproufing 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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