Systems Biology: Offering New Insights into Biomarkers for Precision Medicine and Mechanisms for Cell Signaling
Speaker
Princess Imoukhuede, Ph.D.
Associate Professor
Department of Biomedical Engineering
Washington University in St. Louis
Abstract
Several diseases are attributed to either deficient or excessive vascularization, so understanding angiogenesis offers great promise for improving vascular therapies. Angiogenesis is primarily regulated by vascular endothelial growth factor receptors (VEGFRs), and changes in VEGFR protein expression are promising biomarkers for predicting the efficacy of VEGFR pathway inhibition. However, current quantitative data on VEGFR protein expression in human vessel biopsies are limited, because of both the invasive procedures necessary and difficulty in standardizing non-quantitative measurements across labs. Here, we pioneer a standardized workflow that consists of liquid biopsy-based quantitative flow cytometry and cell-by-cell data analysis. We employed this workflow to establish healthy baselines for VEGFRs on the plasma membranes of two key circulating angiogenic cell populations: circulating endothelial cells (cECs) and circulating progenitor cells (cPCs). Our findings provide new insights into how sex and age influence the distribution of VEGFRs on these circulating angiogenic cells. Additionally, targeting VEGF alone has not achieved the promise of stable vascular control. Angiogenesis involves several signaling axes in addition to VEGF, representing a complexity that cannot be captured by targeting one growth factor alone. Indeed, several non-VEGF growth factors are upregulated after anti-VEGF treatment for cancer therapy, including platelet-derived growth factors (PDGFs). Furthermore, dual growth factor therapy resulted in synergistic effects when used to promote vascularization in animal ischemia models. These combined findings present a compelling need to shift our pedagogy away from a uni-axis understanding of vascularization (e.g., VEGF alone) toward a multi-axis understanding (e.g., VEGF + PDGF). We recently discovered non-canonical, high-affinity binding of platelet derived growth factors (PDGFs) to the primary angiogenic receptor, vascular endothelial growth factor receptor-2 (VEGFR2). Delineating this currently undefined PDGF role in VEGFR2 signaling will provide new tactics for controlling angiogenesis in health and disease. Towards this aim, we computationally model binding and trafficking; experimentally measure signaling and angiogenic function; and molecular interactions. Our mass-action kinetics models predict significant PDGF:VEGFR2 binding when VEGFR2 is overexpressed and during anti-VEGF therapy. Furthermore, PDGF treatment induces cell proliferation, an angiogenic hallmark, and select PDGFs mediate cell migration. Finally, stable PDGF:VEGFR2 binding conformations are observed via molecular dynamics (MD) simulations. Our modeling, signaling, and functional analyses define the importance of PDGF:VEGFR2 signaling. Further exploration of this non-canonical signaling should drive the development of new treatments for angiogenesis-related diseases.
Bio
Professor Imoukhuede is a native of Illinois, having attended Rich South High School and the Illinois Mathematics and Science Academy (IMSA). Professor Imoukhuede earned her SB in Chemical Engineering from the Massachusetts Institute of Technology (MIT) where her research earned her the coveted Class of 1972 award, presented annually to the project that most improves the quality of life through its impact on people and/or the environment. Professor Imoukhuede’s research was funded by the National Science Foundation’s Biotechnology Process Engineering Center at MIT and through a Bioengineering Undergraduate Research Award by the MIT Division of Bioengineering and Environmental Health. Professor Imoukhuede was also an NCAA All-American athlete, garnering these honors three times for placing at the NCAA Track and Field Championships. Professor Imoukhuede was honored with the 2002 Betsy Schumaker Award (also known as the MIT female athlete of the year), was selected to a COSIDA/VERIZON Academic All-America team, and was awarded an NCAA postgraduate scholarship. Professor Imoukhuede championed the importance of social responsibility in the midst of academic excellence by serving as the President of the MIT Committee on Multiculturalism, President of the MIT chapter of the American Institute of Chemical Engineers (AIChE), and held both chapter and zone offices in the National Society of Black Engineers (NSBE).
After earning her undergraduate degree, Professor Imoukhuede pursued graduate study in Bioengineering at the California Institute of Technology (Caltech) in Pasadena, CA. Here, she combined sensitive techniques in biomedical optics with nanoparticle imaging towards understanding the structure, function, and trafficking of a key protein in epilepsy, the GABA transporter, GAT1. She also performed research in nicotine addiction through molecular imaging of nicotinic acetylcholine receptors. Professor Imoukhuede’s research in nanotechnology earned her the Kavli Nanoscience Institute Award and her graduate research was supported by the National Institutes of Health (NIDA). Professor Imoukhuede was the first African-American woman to be awarded a Bioengineering PhD by Caltech and was only the second African-American woman to earn a PhD from Caltech’s Division of Engineering and Applied Science.
Professor Imoukhuede completed a Postdoctoral Fellowship in the Biomedical Engineering Department at the Johns Hopkins University School of Medicine. During her fellowship at Johns Hopkins, she was 1 of 10 postdoctoral fellows nationwide to earn the prestigious United Negro College Fund/Merck Postdoctoral Research Fellowship, 1 of 6 young investigators to earn the FASEB Postdoctoral Professional Development Award, and her work was awarded a Poster Award at the biennial Gordon Conference in Angiogenesis. Her postdoctoral work was also supported by the National Institutes of Health (NHLBI).
Professor Imoukhuede’s biography is featured in the book, A Hand Up: Women Mentoring Women in Science. You can also listen to her story, which was featured in the August 2017 Podcast: People Behind the Science.
