Karen Rakowiecki
Postdoctoral Trainee
Department of Anatomy and Cell Biology
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Advisor: Orly Lazarov
Co-mentor: Jalees Rehman
Title: The role of APP gene overdose in endothelial cell dysfunction in DS
Down syndrome (DS), caused by trisomy 21 (T21), is the most common chromosomal disorder. Cardiopulmonary complications account for over 75% of DS-related deaths. Notably, pulmonary arterial hypertension (PAH) and chronic lung disease can occur without congenital heart disease (CHD). DS lungs exhibit a hypoplastic phenotype marked by impaired alveolarization and persistent double capillary networks. Together, this suggests intrinsic angiogenic defects. Overexpression of the anti-angiogenic gene amyloid precursor protein (APP), encoded on human chromosome 21 (HSA21), has been implicated in these abnormalities. APP knockout in endothelial cells disrupted VEGF-A-mediated functions, including impaired cytoskeletal organization, reduced focal adhesion (FA) and tight junction (TJ) protein expression, and reduced Src-focal adhesion kinase (FAK) signaling. Crosstalk between these kinases, cell adhesion molecules (CAM), and Rho GTPases regulate cytoskeletal dynamics. We hypothesize that APP gene overdose alters Rho GTPase signaling, leading to endothelial dysfunction and impaired angiogenesis in DS. To address this hypothesis, we have differentiated DS MC (mock CRISPR) and APP +/+/- induced pluripotent stem cells (iPSCs) into endothelial cells. Sequencing and biochemical assays will be utilized to assess endothelial cell function and Rho GTPase activity. These studies will define how APP-mediated dysregulation of Rho GTPase pathways contributes to endothelial and angiogenic dysfunction in DS. Elucidating this mechanism will provide new insight into the pathogenesis of pulmonary vascular disease and identify potential molecular targets for therapeutic intervention in individuals with DS.