Abstract
Impaired TGFß signaling is a defining feature of thoracic aortic aneurysm and dissection (TAAD) related disorders, such as Loeys-Dietz syndrome. While pathogenic variants affecting TGFß signaling components are known to underlie these conditions, the precise mechanisms through which these specific variants induce pathology are not fully understood. While vascular smooth muscle cell (VSMC) dysfunction is often implicated due to medial degeneration, endothelial cells (ECs) have been overlooked in this context. Dysregulated endothelial nitric oxide (NO) signaling has been linked to aneurysm development, yet its connection to TGFß signaling remains unclear. This project aims to unravel the TGFß paradox and explore how impaired TGFß signaling impacts NO regulation using in vivo fluorescent light sheet imaging in zebrafish. By employing a unique fluorescent TGFß reporter specific to ECs and VSMCs, we will observe real-time TGFß signaling dynamics in a zebrafish Tgfb2 knockout model. Subsequently, utilizing a novel genetically encoded endothelial NO probe (geNOps), we will investigate the influence of impaired TGFß signaling on NO regulation through in vivo imaging. Finally, we will identify therapeutic targets using a single-cell RNA sequencing approach on the novel zebrafish model we developed. This will bring us closer to a curative therapy for life-threatening TAAD and pave the way for the identification of prognostic biomarkers of aortic disease severity.
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