CAREER: An Integrated Research and Education Program to Investigate Hypoxia and Matrix Remodeling During Stem Cell Differentiation and Lymphatic Morphogenesis

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As an essential part of the circulatory system, the lymphatic vasculatures regulate stability of tissue fluid, adsorption of dietary fat, and trafficking of immune cells. Despite their important role in health and diseases such as cancer, Alzheimer's disease, obesity, and chronic wounds, little is known about the molecular mechanisms regulating lymphatic vessel formation. By designing biomaterials to control stem cell differentiation, this CAREER project seeks to determine the roles of oxygen signaling and environmental cues in regulating lymphatic vessel formation during early development. Ultimately, the proposed research promises to uncover the mechanism underlying lymphatic growth. In addition, the integrated education and outreach programs aim to promote learning at all levels by focusing on early engagement of students in service learning to inspire their interests in STEM fields. This project supports education and broadening participation by: (1) stimulating interests in stem cell research through a science exhibit; (2) introducing middle school students to the emerging field of biomaterials using hands-on modules; and (3) educating high school teachers and students through NSF’s Research Experience for Teachers (RET) on contemporary topics in bioengineering.The investigator’s long-term research goal is to use engineering principles to make breakthroughs in stem cell differentiation and lymphatic vessel morphogenesis, while integrating research with education and training of engineers for the future workforce. Toward this goal, this CAREER project aims to integrate research and education programs dedicated to the transdisciplinary investigation of functional interactions between hypoxia-signaling pathways and matrix-driven cues that are essential for stem cell differentiation into lymphatic endothelial cells (LECs) and eventually their morphogenesis to form lymphatic vasculatures. Specifically, the three fundamental questions to be addressed are: (1) How do changes in oxygen concentrations during the early separation process between the blood and lymphatic networks affect the fate of vascular progenitor cells into LECs? (2) How are matrix types (e.g., hyaluronic acid, collagen) and properties (e.g., stiffness, mesh size, degradation) altered during lymphatic morphogenesis and network assembly in vitro? and (3) What functional interactions occur between hypoxia and matrix-driven cues during lymphatic network assembly? To answer these important questions, the proposed research will utilize a transdisciplinary approach that covers many fields from polymer science to stem cell and lymphatic biology. Collectively, this project will develop fundamental knowledge that can aid in stimulating lymphatic vessel growth, enabling effective and robust cell-based therapies, as well as in vitro models for diseases and drug development.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.