Program Director/Principal Investigator (Last, First, Middle): Yenari, Midori A Project Summary/Abstract Stroke is a significant neurological illness with few effective treatments. Understanding mechanisms underlying stroke pathophysiology may help identify appropriate treatments. Inflammation following stroke is now recognized to potentiate ischemic injury at least acutely, but may be important in clearing necrotic debris and initiating regenerative processes. Triggering receptor expressed by myeloid cells-2 (TREM2) is a recently discovered receptor involved in the innate immune system. TREM2 binds to both bacteria and eukaryotic cells, as well as injured neurons. TREM2 is also expressed on microglia, where it appears to promote the phagocytosis of injured neurons. We have preliminarily found that expression of TREM2 on microglia is upregulated following brain ischemia, and its ligands are present on neurons and astrocytes. TREM2 also appears to have anti- inflammatory properties, which could limit some of the damaging effects of stroke. We propose that TREM2 limits injury due to stroke by promoting the phagocytosis of ischemic brain cells and reduces immune molecule expression.
In Aim 1, we will determine whether TREM2 deficiency leads to worsened injury following experimental stroke and ischemia-like insults, and whether TREM2 signaling occurs in ischemic tissue.
In Aim 2, we will determine whether and how TREM2 is involved in mediating microglial functions such as phagocytosing injured neurons following ischemia like insults. Using in vitro models of ischemia-like injury, we will determine whether TREM2 is involved in the phagocytosis of injured neurons, and whether TREM2 knockdown or its inhibition will prevent this.
In Aim 3, we will determine the contributions of TREM2 functions due to brain resident (microglia) or circulating (macrophages) myeloid cells by utilizing a bone marrow chimera model of stroke. Our overarching hypothesis is thatTREM2 is essential for phagocytosis of injured brain cells, and the clearance of injured tissue is essential to improved outcome from stroke. We hope that our studies will build on our knowledge of the significance of the inflammatory brain response to ischemia. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

Yenari, Midori A Project Narrative Stroke is a significant neurological illness with few effective treatments. Inflammation following stroke is thought to increase damage due to non specific immune reactions causing injury to adjacent healthy brain tissue. However, inflammation may also be important in removing dead tissue and aiding in recovery. How this occurs is not well known, but a new receptor, TREM2 may be important in this process. TREM2 seems to reduce inflammatory proteins, but also encourage phagocytosis, or the process where immune cells remove cellular debris. Understanding how TREM2 affects inflammation during stroke could lead to the identification of appropriate treatments. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Bosetti, Francesca
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Northern California Institute Research & Education
San Francisco
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Kim, Jong-Youl; Kim, Nuri; Yenari, Midori A (2015) Mechanisms and potential therapeutic applications of microglial activation after brain injury. CNS Neurosci Ther 21:309-19
Kawabori, Masahito; Yenari, Midori A (2015) The role of the microglia in acute CNS injury. Metab Brain Dis 30:381-92
Kim, J Y; Kawabori, M; Yenari, M A (2014) Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr Med Chem 21:2076-97
Webster, Corey M; Hokari, Masaaki; McManus, April et al. (2013) Microglial P2Y12 deficiency/inhibition protects against brain ischemia. PLoS One 8:e70927
Kim, Jong Youl; Kim, Nuri; Zheng, Zhen et al. (2013) The 70 kDa heat shock protein protects against experimental traumatic brain injury. Neurobiol Dis 58:289-95
Park, Yu Mi; Lee, Won Taek; Bokara, Kiran Kumar et al. (2013) The multifaceted effects of agmatine on functional recovery after spinal cord injury through Modulations of BMP-2/4/7 expressions in neurons and glial cells. PLoS One 8:e53911
Namura, Shobu; Ooboshi, Hiroaki; Liu, Jialing et al. (2013) Neuroprotection after cerebral ischemia. Ann N Y Acad Sci 1278:25-32
Kim, Jong Youl; Kim, Nuri; Yenari, Midori A et al. (2013) Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular calcium-sensing receptor protect neurons against traumatic brain injury. J Neurotrauma 30:1170-6
Yenari, Midori A; Han, Hyung Soo (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267-78
Kim, Nuri; Kim, Jong Youl; Yenari, Midori A (2012) Anti-inflammatory properties and pharmacological induction of Hsp70 after brain injury. Inflammopharmacology 20:177-85

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