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Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged

Award Number: R01HL163005
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged - ABSTRACT: Aging and age-related diseases like peripheral artery disease (PAD) lead to considerable morbidity and mortality. Aging is associated with impaired inflammatory arteriogenesis responses to injury. We defined a macrophage signaling axis that activates the mRNA stabilizing protein, HuR, to promote VEGF-A expression required for arteriogenesis. We seek to understand the effects of aging on this pathway. Moderately aged (52- week-old) mice demonstrated reduced blood flow recovery and decreased arteriogenesis relative to young (12- week-old) mice in a femoral artery ligation model of ischemia. In aged mice, ischemic muscle tissue and macrophages revealed reduced VEGF-A expression. Aged macrophages demonstrated increased global DNA methylation, and though macrophage HuR expression was normal, there was reduced HuR binding to VEGF-A mRNA with consequent shortened VEGF-A mRNA half-life. Somewhat surprisingly, Dicer1, previously established as destabilizing for VEGF-A mRNA, was downregulated in aged macrophages. The DNMT inhibitor, RG108, led to increased Dicer1 and VEGF-A expression and increased HuR binding to VEGF-A mRNA. miR-29, as a 3p miRNA, appears to be particularly sensitive to changes in Dicer1 expression. Aged macrophages had decreased expression of miR-29, whose seeding site in the 3′-UTR of VEGF-A is adjacent to the HuR binding site. Transfection of macrophages with miR-29 mimic increased VEGF-A expression. Myeloid Dicer1-deleted mice were phenotypically similar to aged mice, having decreased blood flow recovery, decreased VEGF-A expression, and decreased HuR binding to VEGF-A mRNA with consequent shortened mRNA half-life. Our hypothesis is that aging acquired methylation of Dicer1 with consequent reductions in Dicer1 dose-sensitive microRNAs (i.e. miR-29-3p) results in reduced binding of HuR to VEGF-A mRNA and reductions in both VEGF-A expression and consequent VEGF-A dependent angio/ arteriogenesis. Our aims seek to 1) define Dicer1 promoter methylation in aged mice to be a major mechanism of impaired VEGF-A- mediated arteriogenesis with aging; and 2) define the molecular mechanisms whereby the Dicer1 dose- sensitive microRNA, miR-29-3p, promotes HuR-binding to VEGF-A mRNA with consequent message stabilization. Our studies will lead to a paradigm shift from Dicer1 as a negative regulator of VEGF-A to that of a positive regulator. The rescue of macrophage VEGF-A expression by demethylation of Dicer1 or noncoding RNA (i.e. miR-29) mimics, may have profound implications in the development of treatment strategies that can promote arteriogenesis and associated tissue preservation in the setting of severe age-related vasculopathies.


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 = $462,403 )
2025	2025	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	4	4/30/2025	NON-COMPETING CONTINUATION	$462,403
2025	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	3	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $462,403

Issue Date FY: 2024 ( Subtotal = $575,611 )
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	3	3/15/2024	NON-COMPETING CONTINUATION	$466,287
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	3	3/16/2024	SUPPLEMENT FOR EXPANSION	$67,877
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	002	3	6/24/2024	NON-COMPETING CONTINUATION	$41,447
														Subtotal = $575,611

Issue Date FY: 2023 ( Subtotal = $590,115 )
2023	2023	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	2	4/13/2023	NON-COMPETING CONTINUATION	$522,238
2023	2023	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	2	4/14/2023	SUPPLEMENT FOR EXPANSION	$67,877
														Subtotal = $590,115

Issue Date FY: 2022 ( Subtotal = $586,229 )
2022	2022	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	3/25/2022	NEW	$537,039
2022	2022	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Cardiovascular Diseases Research	001	1	8/26/2022	SUPPLEMENT FOR EXPANSION	$49,190
														Subtotal = $586,229

Grand Total All Awards = $2,214,358

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Combining Targeted Demethylation with Noncoding RNA-mediated mRNA Stabilization as a Strategy for Therapeutic Arteriogenesis in the Aged

Award Number: R01HL163005

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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