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Role of miR-146a in Abdominal Aortic Aneurysm

Award Number: R01HL156957
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Role of miR-146a in Abdominal Aortic Aneurysm - Abstract Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with a high mortality greater than 80% after rupture. Aortic vascular smooth muscle cells (SMCs) are pivotal in maintaining aortic structural integrity and function, and SMC-rich aortic medial stability is highly disrupted in AAA. Currently, besides surgical interventions, no alternative therapeutics are available to blunt AAA progression and rupture. Consequently, there is a dire need to identify novel strategies for development of effective, non-surgical therapeutics. MicroRNA-146a (miR-146a), a well-known regulator of inflammation and auto-immunity, is highly expressed in aneurysmal tissue of AAA patients. However, the role of miR-146a in SMC homeostasis and AAA remains to be explored. In preliminary studies, by in-situ hybridization, we observed that miR-146a is upregulated in SMC-rich aortic media of human and mouse AAAs; miR-146a deficiency significantly promoted Angiotensin II (AngII) -induced AAA formation in normolipidemic mice co-administered with Lysyl oxidase inhibitor, β-aminopropionitrile (BAPN); and mimetics-mediated miR-146a overexpression abolished AngII-induced AAAs in both hypercholesterolemic LDLr-/- mice and normolipidemic mice co-infused with BAPN. To elucidate underlying mechanisms, by RNA sequencing, we identified novel targets from miR-146a deficiency experiments: TFIID-31, a TATA binding protein associated factor involved in transcriptional activation and repression, is significantly upregulated; whereas Beclin-1, a gene indispensable for autophagy induction and USP9X, a deubiquitinase critical for Beclin-1 stabilization, are significantly downregulated. Autophagy, a self-regulatory process by which cells digest, and recycle their cytoplasmic materials for energy purposes under stress. Our preliminary study also showed an increased Beclin-1 in mouse AAAs, as observed in human AAAs and Tat-peptide mediated Beclin-1 activation suppressed AngII-induced AAA formation in mice. In addition, miR-146a overexpression significantly suppressed TFIID-31, promoted USP9X and Beclin-1, and ShRNA-mediated silencing of TFIID-31 increased USP9X in cultured aortic SMCs. Based on these observations, we will test our central hypothesis that miR-146a activation protects against AAA formation and progression by promoting Beclin-1-mediated aortic SMC homeostasis. By utilizing our unique mice models generated specifically for these studies, we propose 3 aims. Aim 1 will test our working sub-hypothesis that miR-146a promotes Beclin-1 stability in aortic SMCs via a TFIID-31-USP9X –dependent manner. Aim 2 will test our working sub-hypothesis that miR-146a activation protects against AAA through activation of SMC-Beclin-1-derived autophagy. Aim 3 will determine the effect of miR-146a / Beclin-1 activation on progression of established AAAs. In summary, we will delineate the protective role of Beclin-1 in AAA and establish miR-146a activation as a novel therapeutic strategy against AAA by targeting SMC-Beclin-1. This mechanistic research will set solid preclinical evidence that targeting miR-146a represents a novel therapeutic strategy for treatment and prevention of AAA.


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 = $454,204 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	12/10/2024	NON-COMPETING CONTINUATION	$454,204
														Subtotal = $454,204

Issue Date FY: 2024 ( Subtotal = $494,578 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	002	3	12/14/2023	NON-COMPETING CONTINUATION	$454,205
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	003	3	6/24/2024	NON-COMPETING CONTINUATION	$40,373
2024	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	2	11/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$199,882
2024	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	11/6/2023	NEW	-$199,882
														Subtotal = $494,578

Issue Date FY: 2023 ( Subtotal = $504,672 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	002	2	12/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	2	11/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$454,205
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	003	2	3/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$50,467
2023	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	11/21/2022	NEW	$0
														Subtotal = $504,672

Issue Date FY: 2022 ( Subtotal = $500,050 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	12/7/2021	NEW	$500,050
														Subtotal = $500,050

Grand Total All Awards = $1,953,504

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Role of miR-146a in Abdominal Aortic Aneurysm

Award Number: R01HL156957

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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