Abstract
Thoracic aortic aneurysm and dissection (TAAD), including Marfan syndrome (MFS), is a life-threatening condition driven by genetic mutations and modifiers affecting vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Understanding these genetic modifiers is key to explaining disease variability and identifying new therapeutic targets. This study employs patient-derived induced pluripotent stem cells (iPSCs) and their isogenic controls to model TAAD, differentiating them into VSMCs and ECs. A high-throughput CRISPR knock-out screen will be applied to iPSC-derived VSMCs and ECs harboring pathogenic variants, enabling the identification of key molecular pathways. Functional assays will assess matrix metalloproteinase (MMP2/9) activity, reactive oxygen species (ROS) production, insulin-like growth factor-binding proteins (IGFBP2), and nitric oxide (NO) production. Additionally, RNA sequencing will provide transcriptomic insights. By integrating functional and transcriptomic analyses, this project aims to reveal mechanisms driving TAAD progression and uncover novel therapeutic strategies, paving the way for more targeted and effective treatments.
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