Immune Regulation of the Blood-Brain Barrier - PROJECT SUMMARY The overarching goal of this project is to understand the mechanisms underlying brain-immune interactions at the blood-brain barrier and thereby generate novel targets for immunotherapy in neuroinflammatory conditions. To achieve this goal, I will use an innovative approach that combines genetic manipulation of the brain vascular endothelium in an animal model of viral encephalitis, creating an atlas of immune signaling at the blood-brain barrier, and validation in human tissue. This project will address how inflammatory signals coming from the brain parenchyma are translated across the blood-brain barrier endothelium, and where along the brain vasculature these important immune interactions are occurring. A fundamental understanding of the mechanisms underlying immune cell recruitment to the brain will open the door to novel therapeutics that specifically target immune signaling pathways in the brain. In completing this project, I will gain the critical training and skills necessary to fill the gaps in my current skill set as I transition to an independent investigator. The training goals in this proposal have been carefully crafted to form the foundation for a successful career in basic and translational scientific investigation in neurobiology, immunology, and virology. This plan includes developing expertise in immunophenotyping, single-nucleus and single-cell sequencing, animal models of disease, mouse genetics, and human tissue assays. My training plan also includes specific resources, mentorship, and courses to support my career development as a physician- scientist. To achieve these goals, I have assembled an outstanding mentorship team with scientific expertise in complementary aspects of this project and exemplary track records for training independent investigators and physician-scientists. In addition to my primary mentor Dr. Chenghua Gu, Dr. von Andrian will provide mentorship in vascular biology and immunology. Dr. Quintana will complement these areas of expertise with mentorship in innate immunology, neurobiology, RNA sequencing, and animal models of neuroinflammation. Dr. Knipe will provide expertise in innate immunology and virology, and Dr. Chitnis will continue her outstanding mentorship in human tissue studies and career development as a successful physician-scientist. The institutional resources available through Harvard Medical School and Brigham and Women’s Hospital are world-class and will support my career in an environment that fosters high-impact contributions and interdisciplinary collaborations. Through this comprehensive training plan and carefully selected mentorship team, I will be ideally positioned to be an independent investigator with a unique expertise in the brain-immune interface.
