Victor Aguilar
Postdoctoral Trainee
Department of Pharmacology & Regenerative Medicine
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About
Advisor: Dolly Mehta
Co-mentor: Irena Levitan
Project Title: The role of endothelial S1PR1 in lung injury via modulation of tissue mechanics
Abstract:
Endothelial cell (EC) attachment to the extracellular matrix (ECM), driven by focal adhesion kinase (FAK), is crucial for maintaining a restrictive endothelial barrier by regulating tension transmission to the nucleus and gene transcription. Hence, conditional deletion of FAK in EC impaired the synthesis of barrier-enhancing genes such as KLF2 and S1PR1, leading to barrier disruption, a hallmark of acute lung injury (ALI). ALI is a major clinical problem since when it morphs into acute respiratory distress syndrome (ARDS) it leads to significant morbidity. However, the impact of S1PR1 on cellular stiffening and the progression of lung damage in ALI models has not been characterized. My primary objective is to investigate the role of S1PR1 agonism/antagonism and S1PR1 alterations in regulating cellular stiffening/contractile force generation in the pulmonary vasculature during inflammatory injury. This will be complemented by a comparison between the lungs and the heart vasculature, given their interconnectivity. My second aim will be to sequence ECs at the single-cell level in EC-S1PR1 null mice and control mice, following exposure to LPS without or with S1PR1 agonist/antagonist, as identified in AIM#1, to characterize the impact of S1PR1-driven extracellular matrix mechanics on ARDS in vivo.