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Genomic Regulation and Translational Potential of a Novel Smooth Muscle Cell-Derived Cell Type in Atherosclerosis

Award Number: K99HL153939
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/20/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Genomic Regulation and Translational Potential of a Novel Smooth Muscle Cell-Derived Cell Type in Atherosclerosis - Smooth muscle cells (SMCs) play major roles in atherosclerosis, a leading cause of cardiovascular disease (CVD). SMCs can be beneficial or detrimental in atherosclerosis, depending on their transdifferentiation trajectories into atheroprotective (e.g., fibroblast-like cell) or atherogenic (e.g., macrophage) cell types. My recent work, combining an SMC-lineage tracing murine model and single-cell RNA sequencing (scRNA-seq), revealed a novel SMC-derived cell type, “SEM” cell (termed because of co-expression of stem cell, endothelial cell, and monocyte markers). SMC-derived SEM-like cells have also been identified by other groups. SEM cells highly express genes related to proatherogenic functions (e.g., inflammation) and may be the precursors for other SMC- derived cell types (e.g., fibrochondrocyte, macrophage), through which SEM cells may modulate vulnerability and stability of atherosclerotic lesions. My proof of principle studies in mouse models showed that activation of retinoic acid (RA) signaling inhibited SMC to SEM cell transition, reduced atherosclerotic burden, and promoted fibrous cap stability in atherosclerosis. These findings suggest the following central hypotheses: 1) activation of RA signaling attenuates SMC to SEM cell transition by directly suppressing expression of key SEM cell marker genes; 2) activation of RA signaling represses proatherogenic functions (e.g., inflammation) of SEM cells during disease progression; 3) activation of RA signaling is beneficial in established atherosclerosis and accelerates disease regression by promoting SEM cell atheroprotective functions and differentiation trajectories while suppressing atheroprone features of SEM cells. These hypotheses will be addressed through the following aims: Aim 1 (K99 phase) will determine if RA signaling inhibits the SMC to SEM cell transition via RAR/RXR/EZH2- mediated repression of SEM cell marker genes; Aim 2 (K99 phase) will determine if RA signaling attenuates SEM cell inflammation during atherosclerosis progression through LXR-mediated repression of inflammatory genes; Aim 3 (R00 phase) will apply SMC-lineage tracing and atherosclerosis regression mouse models to determine if RA signaling drives differentiation trajectories of SEM cells towards atheroprotective rather than atherogenic cell types in advanced atherosclerosis (Aim 3A) and promotes SEM cell apoptosis and subsequent resorption via macrophage efferocytosis during disease regression (Aim 3B). The proposed studies will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with scientific and leadership skills that facilitate the successful transition to an independent investigator in the field of atherosclerotic CVD. At the K99 phase, the candidate will continue to obtain expertise in molecular, cellular, and biochemical techniques as well as SMC-lineage tracing and mechanistic and functional investigation of RA signaling and SEM cells in atherosclerosis mouse models for progressing, advanced, and regressing lesions. The expert advisory team will guide the candidate in research training, manuscript and grant proposal preparation, and ultimately in the transition to an independence career over the course of the award period.


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 = $0 )
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	2	5/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $165,456 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	2	12/12/2022	NON-COMPETING CONTINUATION	$165,456
														Subtotal = $165,456

Issue Date FY: 2022 ( Subtotal = $130,842 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cardiovascular Diseases Research	000	1	1/20/2022	NEW	$130,842
														Subtotal = $130,842

Grand Total All Awards = $296,298

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Genomic Regulation and Translational Potential of a Novel Smooth Muscle Cell-Derived Cell Type in Atherosclerosis

Award Number: K99HL153939

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/20/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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