Exploring the roles of Gi and S1Pr1 in endothelial barrier function in vivo

Project: Research project

Description

PROJECT SUMMARY/ABSTRACT. The goal of this Career Development Award is for Dr. Wilsbacher to
develop the skills necessary to successfully become an independent physician-scientist at an academic center.
Dr. Wilsbacher earned her M.D. and Ph.D. degrees in the Medical Scientist Training Program at Northwestern
University, where she investigated genetic and molecular mechanisms that drive circadian rhythms. She
trained in Internal Medicine and Cardiology at the University of California, San Francisco. Dr. Wilsbacher’s
current research objective is to investigate mechanisms of vascular barrier function during normal physiology
and disease, and her long-term career goal is to bridge the gap between circadian physiology and endothelial
function to help advance understanding of mechanisms governing cardiovascular biology and disease.
The training plan includes mentorship by Dr. Shaun Coughlin, a world-class investigator of G proteincoupled
receptor (GPCR) signaling in hemostasis, thrombosis, and vascular integrity who has an established
record of training young investigators to independence. Additional guidance will be provided from an expert
group of scientists who are leaders in GPCR signaling (Dr. Mark von Zastrow), inflammation (Dr. Donald
McDonald), and protein chemistry (Dr. James Wells). Outstanding research facilities and equipment are readily
available. The training plan also incorporates advanced didactic coursework that focuses on cell signaling,
membrane trafficking, protein interactions, and microscopy; attendance at seminar series; participation and
presentation in local and national conferences; and mentored guidance with manuscript and grant preparation.
Treating or preventing inflammation requires thorough understanding of the mechanisms of endothelial
barrier function. The research proposal aims to uncover signaling mechanisms that regulate vascular integrity,
particularly through sphingosine-1-phosphate receptor 1 (S1Pr1) and Gi signaling. Aim 1 investigates the role
of endothelial Gi and S1Pr1 signaling in barrier function. Specifically, genetic mouse models that express
pertussis toxin (which inhibits Gi) in endothelium, express a pertussis-insensitive Gi in endothelium, or
conditionally delete S1Pr1 in adult endothelium will be tested for changes in vascular permeability. Aim 2 uses
a new GPCR activation detection system to probe when and where S1Pr1 is activated in vivo during
inflammation. The new reporter system, which transcriptionally reports on GPCR activation, is an innovative
tool that will be widely applicable to other GPCRs in diverse tissues. Aim 3
Dr. Wilsbacher’s Career Development Award proposal comprises a promising candidate, outstanding
training environment, rigorous training plan, and exciting research proposal that includes an innovative new
tool and focuses on a topic with direct relevance to human health and disease. At the completion of this
Award, Dr. Wilsbacher should have the skills necessary to succeed as an independent investigator.
probes whether caveolae influence
S1Pr1-Gi coupling, and whether S1Pr1 localization in caveolae affects βarrestin-mediated internalization
StatusFinished
Effective start/end date3/2/152/29/16

Funding

  • National Heart, Lung, and Blood Institute (7K08HL105657-05)

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Lysosphingolipid Receptors
Endothelium
Blood Vessels
Caveolae
Research Personnel
Research Design
Inflammation
Arrestin
Mentors
San Francisco
Manuscripts
Whooping Cough
Organized Financing
Genetic Models
Capillary Permeability
Internal Medicine
Circadian Rhythm
Cardiology
Hemostasis
Research