Elucidating the impact of ADAMTS7 on coronary artery disease
Active Project Grant Awarded Last action
- Award ID
- F31HL184820
- Recipient
-
The Trustees Of Columbia University In The City Of New York UEI QHF5ZZ114M72
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Place of performance
- New York, NY 10032, USA
Award details come from USAspending.gov.
Description
- Abstract
- Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the western world, affecting approximately one in three adults. Despite advances in lipid-lowering therapies, ASCVD prevalence continues to rise, highlighting an urgent need for novel therapeutic strategies targeting underlying disease mechanisms. Human genome-wide association studies consistently link ADAMTS7, encoding a matrix metalloproteinase, to ASCVD, but the precise mechanisms through which ADAMTS7 contributes to disease pathogenesis remain unclear. Previous studies indicate ADAMTS7 promotes vascular smooth muscle cell (VSMC) migration and neointimal formation, suggesting an influential role in atherosclerosis. Recent findings demonstrate that VSMC-specific ADAMTS7 overexpression promotes the emergence of a foamy VSMC subpopulation within atherosclerotic lesions due to increased lipid uptake by the vsmcs. This foamy subset notably exhibits upregulated expression of the transcription factor SPI1, implicating SPI1 as a potential downstream mediator of ADAMTS7-driven cellular transitions during atherogenesis. Building directly upon these findings, this project aims to define the mechanisms by which ADAMTS7 influences VSMC phenotypes and promotes ASCVD and the role of SPI1 in this process. I will assess whether SPI1 mediates the proatherogenic effects of ADAMTS7. Mice with VSMC-specific ADAMTS7 overexpression and SPI1 knockout will be evaluated for changes in lesion size, VSMC foam cell formation, and inflammatory responses. Then, I will characterize ADAMTS7-driven transcriptional and epigenetic changes in vascular cells during atherosclerosis using single-nucleus multiome sequencing (SNMULTIOME-SEQ). The analysis will identify cell-type specific gene regulatory networks altered by ADAMTS7 overexpression, focusing on chromatin changes near SPI1 locus. All key findings will be validated in mouse and human vascular tissues through rnascope and immunohistochemistry, addressing discrepancies regarding ADAMTS7'S role in human disease. Collectively, this work will provide novel insights into ADAMTS7-mediated mechanisms of ASCVD, potentially informing new therapeutic interventions targeting VSMC modulation. Overall, this proposal includes comprehensive training in ASCVD genetics, experimental models, and advanced genomic technologies, conducted within a supportive research environment, fostering my development toward an independent scientific career.
Quick answers
Who received award F31HL184820?
F31HL184820 was awarded to The Trustees Of Columbia University In The City Of New York by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.
How much is award F31HL184820 worth?
$50,114 has been obligated on F31HL184820.
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