Current stroke research focuses more on understanding the brain's self-protective and repair mechanisms. It is believed that detailed elucidation of these mechanisms is important as such knowledge could lead to development of pharmacological or other therapeutic interventions to mimic or engage brain's self-protective/repair mechanisms for successful stroke therapy. With the proposed research our contribution is expected to be understanding of the origin, regulation and function of a key brain peptidase neurolysin (Nln) in processes modulating the brain's re-sponse to stroke and its recovery after stroke. The importance of studying function of Nln in the post-stroke brain is signified by its sustained functional upregulation in the mouse brain for at least 7 days after stroke, and ability of Nln to inactivate several neurotoxic and to generate three cerebro-protective/regenerative peptides. Based on published and preliminary experimental evi-dence from our laboratory, we hypothesize that upregulation of Nln following stroke is a regulat-ed process involving both neurons and astrocytes, and plays a critical role in brain's response to stroke and its recovery after stroke in mice. Our hypothesis will be tested in two specific aims. Aim 1: Identify the main regulatory mechanisms responsible for induction of extracellular Nln following ischemia in vitro. Working hypothesis: Ischemia will induce translocation of cytosolic Nln to the plasma membrane in neurons, and secretion of Nln from astrocytes by modulating intracellular calcium ions and cAMP, respectively. Aim 2: Determine the therapeutic potential of Nln in post-stroke brain protection and recovery using an in vivo model of stroke. Working hy-pothesis: Delivery of recombinant Nln to the post-ischemic brain will provide cerebroprotection and promote functional recovery and brain repair after stroke. The proposed studies will have substantial impact on the stroke research field because they 1) will identify a novel, endogenous mechanism of self-protection and repair in the post-stoke brain, and 2) will investigate the po-tential of Nln to be a therapeutic target modulating function of multiple targets, i.e. neuropeptides, critically involved in various pathways responsible for ischemic brain injury or repair. This new knowledge could provide a foundation for development of novel strategies to treat human ischemic stroke.
|Program type||Beginning Grant-in-Aid|
|Effective start/end date||07/01/2014 → 06/30/2016|