Rotation Projects

Project 1. “Stress failure” of pulmonary capillaries in response to high pulmonary microvessel pressure experienced in patients with left heart failure, head trauma, or high altitude is an important mechanism in the loss of endothelial barrier function. The most recent work from out laboratory indicates that high hydrostatic pressure activates a mechanosensing ion channel Piezo1 in endothelial cells (EC) of microvessels leading to calpain-dependent degradation of VE-cadherin and associated catenin proteins. These findings have for the first time linked increased tension to which ECs are exposed to the activation of Piezo1 and disassembly of AJs. This potentially important role of Piezo1 raises the fundamental questions: (i) “does tension regulate Piezo1 dynamics at the plasma membrane (PM) of ECs and if so how?” and (ii) “whether post-translational modification of Piezo1 is required for continues sensing of hydrostatic pressure by ECs?” The research project will delineate the signaling pathways regulating Piezo1 activity in ECs. The studies will involve integrated approaches in live super-resolution imaging, cell biology, proteomic analysis, biochemistry and lung microvessel physiology.

Project 2. ARDS remains one of few lung diseases with no pharmacological treatment, and standard care for patients remains largely supportive. We have taken a novel approach to address ARDS by limiting pathological capillary leakage, a common underlying factor in all forms of ARDS. Our recent studies have led to the discovery of therapeutic candidate that combats ARDS through suppression of pathological vascular leakage in the lung. This therapeutic candidate promptly restores lung tissue-fluid homeostasis and lung mechanics, reduces lung inflammation, mitigates pulmonary fibrosis associated with ARDS, and markedly improves animal survival. The research project will investigate how this therapeutic candidate promotes resolution of ARDS in mice. The studies will involve integrated analyses of gene expression profile of pulmonary endothelial cells of mice challenged with endotoxin with and without treatment with therapeutic candidate.

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