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MicroRNAs, Mitochondria and the Blood-Brain Barrier - Therapeutic Targets for Stroke

Award Number: R01NS117606
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: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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MicroRNAs, Mitochondria and the Blood-Brain Barrier - Therapeutic Targets for Stroke - Project Summary/Abstract Stroke is a debilitating disease, affecting >15 million people worldwide annually, the majority of which are over 65 years old. Developing effective treatments for older stroke patients remains a pressing need. Stroke causes disruption of the blood-brain barrier (BBB) to brain damage, hemorrhagic transformation (HT), and worse functional outcomes. We have discovered that mitochondrial energy production in cerebrovascular endothelial cells (CECs) plays a central role in maintenance of BBB integrity both in in vivo and in vitro models. We have found altered levels of several microRNAs (miRNAs) in plasma and primary CECs (pCECs) from aged stroke mice. Specifically, expression of miR-34a is upregulated in both the plasma and pCECs from aged stroke mice compared with sham controls. Notably, miR-34a is also upregulated in plasma from stroke patients compared to healthy controls. Overexpression of miR-34a in murine CECs (mCECs) increases BBB permeability, compromises mitochondrial oxidative phosphorylation (OxPhos), and reduces mitochondrial membrane potential (ΔΨm) while decreasing the levels of several mitochondrial related genes; Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) in human CECs (hCECs) and LETM domain containing 1 (LETMD1) in mCECs. Importantly, our preliminary data show that LETM1 is significantly reduced in CECs in autopsy samples from stroke patients compared with controls. Additionally, we have shown that global knockout of miR-34a (miR- 34a–/–) reduces infarct size and conversely, overexpression of miR-34a (miR-34aTG) increases infarct size in mice. Similarly, systemic delivery of antagomiR-34a (a miR-34a inhibitor) reduces infarct size and improves long-term functional recovery in stroke mice. Although our findings provide compelling evidence that miR-34a plays an important role in stroke pathophysiology, the mechanism by which endothelial miR-34a mediates brain damage is unknown, especially in aged models of stroke. The objective of this proposal is to investigate if endothelial specific miR-34a affects stroke outcomes in the aged brain. We hypothesize that endothelial miR-34a regulates BBB permeability, ischemic damage, hemorrhagic transformation, and stroke-induced deficits by inhibiting translation of LETM1 and LETMD1 leading to impaired mitochondrial bioenergetics in CECs. Aim 1 will test if endothelial specific knockout of miR-34a improves acute and long-term stroke outcomes in aged mice of both sexes. Aim 2 will identify a mechanism by which miR-34a inhibits translation of LETM1 and LETMD1 leading to impaired mitochondrial function in CECs following stroke. Aim 3 will determine the therapeutic potential of nanoparticle delivery of endothelial cell targeted miR-34a antagomir in aged stroke mice of both sexes. Our studies will elucidate the role of endothelial miR-34a in stroke. Understanding the preclinical effects of endothelial specific antagomiR-34a treatment is an important step in the development of novel therapies for elderly stroke patients.


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: 2026 ( Subtotal = $453,397 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/16/2026	NON-COMPETING CONTINUATION	$408,058
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/18/2026	NON-COMPETING CONTINUATION	$45,339
														Subtotal = $453,397

Issue Date FY: 2025 ( Subtotal = $408,058 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2024	NON-COMPETING CONTINUATION	$408,058
														Subtotal = $408,058

Issue Date FY: 2024 ( Subtotal = $439,797 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/28/2023	NON-COMPETING CONTINUATION	$408,058
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/3/2024	NON-COMPETING CONTINUATION	$31,739
														Subtotal = $439,797

Issue Date FY: 2023 ( Subtotal = $453,397 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/30/2022	NEW	$453,397
														Subtotal = $453,397

Grand Total All Awards = $1,754,649

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MicroRNAs, Mitochondria and the Blood-Brain Barrier - Therapeutic Targets for Stroke

Award Number: R01NS117606

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: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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