CARDIOVASCULAR DRUG DISCOVERY LAB (CAP)
PI- Dr. Santosh Karnewar
Our long-term goal is to identify novel therapeutic targets in cardiovascular diseases, particularly atherosclerosis, myocardial infarction, and stroke. We focus on understanding the mechanisms driving atherosclerosis and developing interventions for age-associated disease. Special emphasis is placed on the role of inflammation and aging (Inflammaging) and its impact on disease progression and therapy.
Our lab will investigate the cellular and molecular mechanisms that drive disease progression, emphasizing age-associated atherosclerosis and the inflammatory processes that exacerbate vascular pathology. By combining advanced SMC and EC- lineage tracing mouse models, scRNASeq, cy-TOF, and Ultrasound echo techniques, and mechanistic studies, we aim to understand how smooth muscle cells, endothelial cells, and immune cells contribute to plaque development, progression, and regression. Our recent work has highlighted the complex roles of senescence and IL-1β–dependent pro-inflammatory signaling in late-stage atherosclerosis. Furthermore, our novel mouse model of myocardial infarction, plaque rupture, and stroke will play key role in our studies. Unlike traditional Apoe-/- and Ldlr-/- models, these mice develop spontaneous plaque rupture, MI, stroke, and increased mortality in response to Western diet (WD) feeding, closely mimicking human coronary artery disease (CAD) in aged patients.
Cellular senescence accumulates in the vascular wall with age and drives atherosclerosis by promoting inflammation through the senescence-associated secretory phenotype (SASP). Senolytic agents, which selectively eliminate senescent cells, have shown promise in reducing plaque burden and vascular inflammation in early-stage disease. However, in advanced atherosclerosis, removing senescent vascular cells can destabilize plaques and impair smooth muscle–mediated repair, increasing cardiovascular risk. These findings highlight the complex, stage-dependent role of senescence and the need for precision-targeted senolytic/senomorphic therapies in atherosclerosis.
By leveraging these novel lineage-tracing mouse models, we aim to investigate the role of IL-1β–NFκB–NLRP3 signaling and stress-induced premature senescence (SIPS) versus replicative senescence in smooth muscle cells, endothelial cells, and immune cells to identify novel therapeutic strategies for treating heart attack and stroke.
