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The role of nitrogen metabolism in smooth muscle cell phenotypic plasticity

Award Number: F31HL165772
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/19/2022
PERIOD OF PERFORMANCE END DATE: 12/18/2025

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The role of nitrogen metabolism in smooth muscle cell phenotypic plasticity - Coronary artery is the leading cause of death in the US. While lipid-lowering and anti-hypertensive drugs have helped decrease CAD-related mortality by approximately 50% since the 1980s, these therapies only modify CAD risk factors. To date, no approved drug acts at the vascular wall directly against atherosclerosis, the underlying cause of CAD. One opportunity to develop novel therapies is through genetics: CAD is partially heritable, and recent genome-wide association studies identified over 200 loci associated with elevated risk for CAD. While 40% of these CAD loci having established associations with known risk factors, the molecular and cellular mechanisms of the remaining 60% of the CAD loci are unknown. The majority of these unknown loci are predicted to function by regulating gene expression in the vascular wall where the disease develops. Vascular smooth muscle cells (SMCs), which make up the medial layer of arteries, play a critical role in the progression of atherosclerosis, the precursor to coronary artery disease. During initiation and progression of atherosclerosis, SMCs transdifferentiate from a quiescent (healthy) phenotype to a proliferative (pathological) phenotype representative of myogenic, osteochondrogenic, and macrophage-like phenotypes that contribute to plaque build-up. Identifying the molecular mechanisms driving SMC phenotypic plasticity will open up new avenues of treatment for CAD. Preservation analysis of co-expression networks from RNAseq data generated from the ascending aortas of 151 multi-ethnic smooth muscle cell donors cultured in quiescent and proliferative conditions, respectively, revealed phenotype-specific network architecture enriched for nitrogen metabolic processes. Previous studies have shown that metabolic pathways are not only involved in phenotypic changes of other cell types in the vascular wall, but also have the capability to drive them. Therefore, the goal of this proposal is to characterize the role nitrogen metabolism plays in SMC phenotypic plasticity and identify the key regulatory genes driving dysregulation. The project will address this problem through 2 aims. In aim 1, I will characterize the role nitrogen metabolism plays in SMCs during the progression of atherosclerosis using a combined approach of metabolomics, cell type marker identification, and cellular phenotyping assays in response to activation or silencing of the nitrogen metabolism pathway. In aim 2, I will create Bayesian networks (BNs) of genes involved in nitrogen metabolic processes using gene expression data and transcription factor-gene expression relationships generated from time-series experiments linking differentially expressed ATACseq peaks and differentially expressed RNAseq peaks in response to pro-atherogenic stimulus. I will then identify the key driver genes (KDs) of nitrogen metabolic pathways whose expression regulates the changes across the gene expression networks. Gain-of-function and loss-of-function experiments for KDs in SMCs using lentiviral particles will be completed with cellular phenotyping assays to quantify the impact on SMC proliferation, migration, and de-differentiation.


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 = $41,012 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	12/11/2024	NON-COMPETING CONTINUATION	$40,448
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	3	7/27/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $41,012

Issue Date FY: 2024 ( Subtotal = $40,448 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	2	9/6/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	12/18/2023	NON-COMPETING CONTINUATION	$39,168
														Subtotal = $40,448

Issue Date FY: 2023 ( Subtotal = -$326 )
2023	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	1	12/26/2022	NEW	$0
2023	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	12/26/2022	NEW	-$326
														Subtotal = -$326

Issue Date FY: 2022 ( Subtotal = $38,552 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	8/17/2022	NEW	$38,552
														Subtotal = $38,552

Grand Total All Awards = $119,686

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The role of nitrogen metabolism in smooth muscle cell phenotypic plasticity

Award Number: F31HL165772

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/19/2022

PERIOD OF PERFORMANCE END DATE: 12/18/2025

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