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Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases

Award Number: R35HL155988
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases - PROJECT SUMMARY Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic disease characterized by lipid retention and vascular inflammation. Endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages are recognized to have a unique impact on the disease progression. It is recently recognized that specific dysregulation of metabolic signaling pathways contributes to certain aspects of EC, macrophage and SMC homeostasis. For instance, during the process of atherosclerosis, ECs are exposed to a pro-inflammatory milieu that enhances glycolysis and reduces fatty acid oxidation in ECs and predisposes them to undergo mesenchymal transition (EndMT), which may affect plaque stability. The implications of non-coding RNAs, including microRNAs (miRNAs), in cardiovascular disease is well recognized, representing the most rapidly evolving research field. Furthermore, miRNAs have emerged as critical regulators of cellular metabolism (e.g. miR-33) and therefore can directly regulate EC metabolic responses that can determine the progression of atherosclerosis, although this aspect has not been elucidated yet. Moreover, miRNAs can promote the acquisition of mesenchymal markers (e.g. miR-21) that can in turn shape their metabolic response and mesenchymal phenotype, thus affecting EC atherosclerotic phenotype. This has also not been investigated in detail. In this regard, similar mechanisms may be involved in the phenotypic regulation of SMC during atherosclerosis, and need to be explored as well. A vast literature has demonstrated that miRNAs play important roles in macrophage functions by regulating macrophage inflammatory responses and lipid metabolism. Increasing evidence indicates that a substantial crosstalk exists between innate immune signaling and metabolic pathways. Macrophage activation and differentiation prominently feature the modulation of genes involved in general cellular metabolic activities. In this regard, downregulation of cholesterol biosynthetic genes in classically activated macrophages is linked to regulation of inflammatory reactions elicited by macrophages. A critical outstanding question is how the dynamic interplay between cholesterol, cholesterol biosynthetic intermediates and cholesterol derivatives influences macrophage foam cell formation and inflammation, which are key determinants of atherosclerosis progression. On the whole, this research program aims to elucidate different mechanisms that regulate cell-specific metabolic signaling pathways and how they are involved in the progression of atherosclerosis. Targeting cell-specific metabolic processes could become another potential therapeutic targeting strategy for treating metabolic disorders.


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 = $929,229 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	6	2/16/2026	NON-COMPETING CONTINUATION	$900,783
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	6	3/19/2026	NON-COMPETING CONTINUATION	$28,446
														Subtotal = $929,229

Issue Date FY: 2025 ( Subtotal = $948,192 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	002	5	8/5/2025	NON-COMPETING CONTINUATION	$94,819
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	5	4/12/2025	NON-COMPETING CONTINUATION	$0
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	5	12/10/2024	NON-COMPETING CONTINUATION	$853,373
														Subtotal = $948,192

Issue Date FY: 2024 ( Subtotal = $929,229 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	002	4	6/14/2024	NON-COMPETING CONTINUATION	$75,856
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	4	12/15/2023	NON-COMPETING CONTINUATION	$853,373
2024	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	3	11/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $929,229

Issue Date FY: 2023 ( Subtotal = $948,192 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	3	1/11/2023	NON-COMPETING CONTINUATION	$853,373
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	3	3/3/2023	NON-COMPETING CONTINUATION	$94,819
														Subtotal = $948,192

Issue Date FY: 2022 ( Subtotal = $948,192 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	2	6/15/2022	NON-COMPETING CONTINUATION	$94,820
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	2	12/21/2021	NON-COMPETING CONTINUATION	$853,372
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	002	2	8/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $948,192

Issue Date FY: 2021 ( Subtotal = $936,044 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	1	1/15/2021	NEW	$936,044
														Subtotal = $936,044

Grand Total All Awards = $5,639,078

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Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases

Award Number: R35HL155988

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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