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Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury

Award Number: R01NS119538
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury - Project Summary/Abstract The cerebral ischemia/reperfusion (I/R) injury is a major challenge for the treatment of patients with acute ischemic stroke by intravenous (IV) thrombolysis and endovascular therapy. Currently, there is no effective intervention available to treat/prevent cerebral I/R injury. Emerging evidence suggests that thrombotic and inflammatory responses (thrombo-inflammation) and aberrant endoplasmic reticulum (ER) stress in the brain elicited by cerebral I/R contributes importantly to secondary brain injury and neurologic deterioration. In this proposal we wish to develop a novel miRNA-based therapeutic strategy to simultaneously target these pathological processes of cerebral I/R injury through distinct molecular mechanisms. Recently, decreased expression of miR-30c has been implicated in many pathological conditions in both patients and animal models. In preliminary studies, we show that miR-30c is highly expressed in blood platelets, cerebral microvessels, and cortical/hippocampal neurons in normal mice but its levels decline with age. miR-30c levels in both blood and brain are markedly decreased after ischemic stroke and elevating miR-30c by single IV injection of synthetic miR-30c mimic significantly protects against cerebral I/R injury. We further show that the increased expressions of the direct target genes of miR-30c (including PAI-1 in both blood and brain, elF2α and caspase-3 in the brain) induced by cerebral I/R injury were significantly decreased by IV miR-30c mimic treatment. Based on these exciting new findings from young adult mice, we propose the innovative hypothesis that miR-30c functions as a critical regulator of thrombo-inflammation and ER stress in the ischemic brain elicited by cerebral I/R injury, and thus targeting miR-30c represents a novel therapeutic approach for combating cerebral I/R injury. Following updated stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines, we will test this hypothesis in aged male and female mice. Specifically, we will determine the efficacy and safety of IV miR-30c mimic as novel stroke therapeutics (Aim1). Using complementary approaches, i.e. the “gain-of-function” (miR- 30c mimic) and “loss-of-function” (anti-sense Morpholino oligos that are designed to specifically compete with miR-30c for binding sites of 3’UTR of each individual target gene and thus acts as a “target protector”), we will identify PAI-1 as a key molecular target of miR-30c in regulation of post-stroke thrombo-inflammation (Aim 2), and identify elF2α and caspase 3 as key molecular targets of miR-30c in regulation of post-stroke neuronal ER stress and neuronal cell death (Aim 3). The long-term goal of these studies is to evaluate if targeting miR-30c is a viable option for stroke therapy in both male and female older populations at high risk for stroke.


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 = $601,657 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/30/2025	NON-COMPETING CONTINUATION	$601,657
														Subtotal = $601,657

Issue Date FY: 2024 ( Subtotal = $583,607 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/28/2024	NON-COMPETING CONTINUATION	$583,607
														Subtotal = $583,607

Issue Date FY: 2023 ( Subtotal = $601,657 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/6/2023	NON-COMPETING CONTINUATION	$601,657
														Subtotal = $601,657

Issue Date FY: 2022 ( Subtotal = $597,643 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/18/2022	NON-COMPETING CONTINUATION	$597,643
														Subtotal = $597,643

Issue Date FY: 2021 ( Subtotal = $597,643 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/31/2021	NEW	$597,643
														Subtotal = $597,643

Grand Total All Awards = $2,982,207

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Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury

Award Number: R01NS119538

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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