Endothelial Senescence in Impairment of Lung Regeneration in Obesity

Project Description Narrative:

Obesity is increasing worldwide. In the U.S., approximately 67% of the adult population is obese (body mass index (BMI) ≥30) or overweight (BMI between 25-30). In Wisconsin, approximately 68% of adults suffer from obesity/overweight. Obesity is a risk factor for increased morbidity and mortality through its association with cardiovascular disease, type 2 diabetes, and cancer, and these are leading causes of death in Wisconsin (CDC 2017). Obesity is also a known risk factor for respiratory diseases including acute lung injury, asthma, and chronic obstructive pulmonary disease. Costs associated with treating obesity-related diseases are approximately $150 billion/year in the U.S. and $3.1 billion/year in Wisconsin and going up.

Lung transplantation is one of the options to save patients with end-stage lung diseases; however, it is not an optimal approach due to a shortage of donors, high cost, serious complications, and a limited graft survival rate. Obesity is associated with poor outcomes in lung transplantation; obesity is currently a relative contraindication to adult lung transplantation. There is a need to identify more efficient strategies for obesity-associated lung diseases. Restoring the intrinsic regenerative and repair ability of the lungs after resection of injured lungs could be a promising strategy for obese patients.

This project seeks to delineate the role of Endothelial Cell (EC) signaling in post pneumonectomy regenerative lung growth in obesity in a preclinical transgenic mouse model; define the new molecular signatures of lean vs. obese mouse lungs during post-PNX lung growth using an unbiased single cell transcriptomic approach; and identify a novel translational extracellular vesicle (EV)-based regenerative strategy using human lung ECs isolated from lean vs. obese patients. If this study demonstrates the role of EC senescence in regenerative lung growth in obesity and proves the regenerative effects of human EC-derived EVs, this work will lead to the development of more efficient EV-based strategies (e.g., senolytics in EVs) to restore lung regeneration in obese adults.