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MiR-409-3p Regulates Angiogensis, Brown Fat Adiposity and Insulin Resistance

Award Number: R01HL149999
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
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: 05/31/2025

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MiR-409-3p Regulates Angiogensis, Brown Fat Adiposity and Insulin Resistance - PROJECT SUMMARY/ABSTRACT White and brown adipose tissues are highly vascularized organs, capable of plasticity based on metabolic demands and energy expenditure. However maladaptive regulation of these tissues can lead to insulin resistance. Critical gaps remain in our understanding of how angiogenesis impacts adipose tissue dysfunction and overall metabolism. MicroRNAs (miRs) are implicated in the regulation of the angiogenic response to pathophysiological stimuli. The role of miRs in regulating the angiogenic response in diet-induced insulin resistance is poorly understood. Using a miRNA-Seq approach, we identified that miR-409-3p expression was significantly increased in endothelial cells (ECs) of brown adipose tissue (BAT) of diet-induced obese (DIO) mice and in human diabetic plasma samples compared to non-diabetic patients. Overexpression of miR-409-3p markedly inhibited EC growth and migration, whereas miR-409-3p inhibition had the opposite effects. Preliminary studies indicate that miR-409-3p targets the 3’UTRs of Zinc Finger E-box binding Homeobox 1 (ZEB1) and Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3). Overexpression of miR-409-3p decreased ZEB1 and MAP4K3 expression in ECs, whereas inhibition had the opposite effect. SiRNA knockdown of ZEB1 or MAP4K3 expression in ECs phenocopied the effects of miR-409-3p overexpression and significantly decreased EC proliferation and migration. 3T3-L1 cells or human skin fat organoids co-cultured with supernatant harvested from ECs overexpressing miR-409-3p had decreased expression of brown adipocyte markers (UCP1, Cidea) by RT-qPCR and Western blot analyses, whereas supernatant harvested from ECs deficient in miR-409-3p increased expression of brown adipocyte markers. Systemic intravenous delivery of LNA-anti-miR-409-3p inhibitor to DIO mice significantly increased angiogenesis by CD31 staining, accompanied by higher UCP-1 in BAT and sWAT by RT-qPCR, Western blot, and immunohistochemistry analyses, while improving glucose and insulin tolerance and overall metabolism. Therefore, we hypothesize that miR-409-3p serves as a critical regulator of EC growth and angiogenesis in adipose tissue and may improve metabolic dysfunction in DIO. To explore this, we first propose in Aim1 to investigate the molecular mechanisms by which miR-409-3p regulates EC growth and angiogenesis. In Aim2, we will delineate the mechanisms by which miR-409-3p in ECs regulates browning in adipose tissues. Finally, in Aim3, we will explore the effect of miR-409-3p neutralization in the vasculature of adipose tissues and development of DIO and insulin resistance in mice. Successful completion of these studies will shed insights on the regulatory role of miR-409-3p between impaired angiogenesis in diet-induced obesity and adipose tissue dysfunction, an effect that could be exploited for therapeutic intervention in obesity-induced insulin resistance.


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: 2024 ( Subtotal = $598,681 )
2024	2024	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	5/7/2024	NON-COMPETING CONTINUATION	$598,681
														Subtotal = $598,681

Issue Date FY: 2023 ( Subtotal = $610,898 )
2023	2023	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	5/11/2023	NON-COMPETING CONTINUATION	$610,898
														Subtotal = $610,898

Issue Date FY: 2022 ( Subtotal = $614,518 )
2022	2022	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	4/28/2022	NON-COMPETING CONTINUATION	$614,518
														Subtotal = $614,518

Issue Date FY: 2021 ( Subtotal = $635,914 )
2021	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	4/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$635,914
2021	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	003	2	7/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$564,963
2021	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	002	1	7/2/2021	NEW	-$564,963
2021	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	4/13/2021	NEW	$0
														Subtotal = $635,914

Issue Date FY: 2020 ( Subtotal = $603,299 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	7/20/2020	NEW	$603,299
														Subtotal = $603,299

Grand Total All Awards = $3,063,310

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MiR-409-3p Regulates Angiogensis, Brown Fat Adiposity and Insulin Resistance

Award Number: R01HL149999

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

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: 05/31/2025

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