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MicroRNA210 and neuroinflammation in acute brain injury of ischemic Stroke

Award Number: R21NS126583
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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MicroRNA210 and neuroinflammation in acute brain injury of ischemic Stroke - PROJECT SUMMARY lschemic stroke is the major type of stroke with high mortality and morbidity, and the health care costs are exorbitant and result in a significant societal burden. Currently although limited therapies including thrombolysis and endovascular clot removal have been approved for the treatment of acute ischemic brain injury, many patients still die or remain disabled. Underlying mechanisms remain poorly understood, hindering the development of effective and specific treatments for this health concern. Thus, there is an urgent need to further investigate the molecular mechanisms and identify effective therapeutic targets. Neuroinflammation is a critical contributor to the pathophysiology of acute ischemic brain injury, in which microglial activation plays a central role. We have recently discovered that microRNA210 (miR210) inhibition significantly reduced brain microglial activation and inflammatory response post-stroke in mice. Our preliminary data also showed miR210 mimic transfection upregulated pro-inflammatory cytokine in primary microglia, and miR210 inhibition reduced the expression of pro-inflammatory cytokine IL-1 f3 after oxygen-glucose deprivation (OGD). These findings suggest a new mechanism of miR210 in microglial inflammatory response contributing to ischemic brain injury. The mitochondria are a major target of miR210 during hypoxia and reprogramming of mitochondrial metabolic switch from oxidative phosphorylation to glycolysis contributes to pro-inflammatory microglial activation. We and others have demonstrated that miR210 reduces mitochondrial oxidative phosphorylation by negatively regulating a number of electron transport chain (ETC)-related genes in multiple cells and increases mitochondrial dysfunction. However, whether miR210 promotes metabolic shift in hypoxic mitochondrial respiration in favor of glycolysis and drives pro-inflammatory microglial response in the setting of stroke is unknown and requires further investigation. Thus, this proposal will attempt to reveal the mechanistic links of metabolic reprogramming in miR210-mediated pro-inflammatory microglial activation in ischemic brain injury. We will evaluate the mechanism of miR210-mediated mitochondrial metabolic shift in programming of proinflammatory microglia and neurotoxicity. We will also determine whether and to what extent miR210 deficiency inhibits microglial mitochondrial dysfunction and reduces neuroinflammation after acute ischemic brain injury. We expect to generate unique insights into the novel role of epigenetic mechanism in the activation of microglial pro-inflammatory phenotype through metabolic shift in the brain post-stroke. The outcome of this study will delineate the mechanism of miR210 in driving microglial inflammatory response. It represents a major breakthrough and paradigm-shifting focus of research and will provide new visions into a novel target of miR210 in potential therapeutic strategies for acute ischemic brain injury.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/5/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $443,438 )
2023	2023	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/12/2022	NEW	$443,438
														Subtotal = $443,438

Grand Total All Awards = $443,438

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MicroRNA210 and neuroinflammation in acute brain injury of ischemic Stroke

Award Number: R21NS126583

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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