Program Director/Principal Investigator (Last, First, Middle): Project Summary/Abstract This project will explore calcium-release-activated calcium channels (CRAC) as a potential therapeutic target in a laboratory stroke model. Stroke is a significant health problem in developed nations, but definitive treatments are few, and no treatments are available which can rescue brain cells dying from ischemia. Microglia are the brain's resident immune cell, and many studies have now shown that when activated, they contribute negatively to stroke outcome. Thus, strategies to inhibit microglial functions could prove therapeutic. Recent work by other labs has focused on the role of CRAC channels in inflammatory cells such as T cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to microglia or inflammation in the ischemic brain. Preliminary work in our lab showed that these inhibitors block microglial activation and protect the brain from experimental traumatic brain injury. This project will study novel inhibitors of CRAC channels in an in vivo model of stroke. Mice exposed to middle cerebral artery occlusion will be treated with novel CRAC channel inhibitors to see if this will improve neurological outcomes, and if this is due to an anticipated anti-inflammatory effect. This project will explore whether this compound will improve outcome in experimental stroke in both male and female animals. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

Public Health Relevance

Project Narrative Stroke is a significant neurological illness with few effective treatments. Inflammation following stroke is thought to worsen damage due to non specific immune reactions causing injury to adjacent healthy brain tissue. Work from our group has focused on these immune reactions, and how they might be modulated to lead to improved neurological outcomes from experimental stroke and brain trauma. Recently, we turned out attention to a recently discovered calcium-release-activated calcium (CRAC) channel, which is present on many types of immune cells throughout the body. Much of the research in this area has focused on inflammatory conditions affecting other parts of the body, but now it is recognized that CRAC channels are present on microglia, the brain's resident immune cell, and CRAC channels seem to cause microglia to activate and express inflammatory molecules. By using novel inhibitors of this channel, developed by biotechnology company, CalciMedica, we could prevent microglia from activating, and, as a consequence, improve outcome from experimental brain trauma. Now we hope to study this same approach in an experimental stroke model, to test whether this approach may prove to be a viable therapeutic approach to treat stroke patients. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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Northern California Institute Research & Education
San Francisco
United States
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Mizuma, Atsushi; You, Je Sung; Yenari, Midori A (2018) Targeting Reperfusion Injury in the Age of Mechanical Thrombectomy. Stroke 49:1796-1802
Kim, Jong Youl; Han, Yeonseung; Lee, Jong Eun et al. (2018) The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke. Expert Opin Ther Targets 22:191-199