Collaborative Research: Quantitative analysis and modeling to determine the role of lipids in lymphatic permeability

Saint Louis University, Saint Louis MO

Investigators

Abstract

The lymphatic system plays a crucial role in keeping tissues in the body balanced by filtering and absorbing fluids, monitoring which cells enter a tissue, and transporting dietary fats into the bloodstream. Sometimes, vessels in the lymphatic system can become leaky. Though helpful in certain conditions, when this leakiness continues for too long, it can slow down the flow of lymph fluid, leading to excess fat buildup, tissue scarring, and persistent inflammation, which are common in many chronic diseases. This project aims to use both mathematical modeling and experiments to understand what regulates leakiness in the lymphatic system. Results from this project will ultimately guide approaches to control the lymphatic system. To broaden the impact of this project to society, high school students will participate in 10-week summer research projects that will enrich their educational training and provide a path to contribute to scientific research. The goal of this project is to develop an integrated computational and experimental engineering-based approach to determine strategies to modulate lymphatic permeability. Using a systems biology approach that iterates between experiments and modeling, the PIs will develop the first models that determine how lipids regulate CD36 (a long-chain fatty acid (FA) translocase) turnover, lymphatic vessel integrity, and cell signaling. Mechanistic differential equation modeling and data-driven regression modeling will be used to simulate the effects of CD36 across scales. Biotinylated surface assays, immunofluorescence microscopy, direct measurements of LEC permeability, and morphological assessment of LEC junctions will be used to inform and calibrate the models. The experimentally validated models will be applied to predict strategies to modulate lymphatic permeability. More broadly, the mechanistic, quantitative, and multiscale understanding of how CD36 regulates lymphatic permeability produced in this project represents significant advances in lymphatic biology and bioengineering that can be leveraged to address pathological changes in several diseases, e.g., obesity and the metabolic syndrome. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.