Move, Eat, Trap, or Kill: Decoding the molecular logic used by innate immune cells to decide between functional programs - Project Abstract/Summary Candidate: I am a joint postdoctoral scholar in the laboratories of Drs. Morgan Huse (Memorial Sloan Kettering Cancer Center), Jason Cyster (UCSF/HHMI), and Orion Weiner (UCSF). My previous PhD research provided extensive training in infectious diseases, humanized mice and other types of advanced infection mouse models, chemistry, and computational biology. This background will be helpful as I investigate how myeloid cells control plasma membrane homeostasis and how plasma membrane abundance functions as an integrator to discriminate between the cellular programs of migration, phagocytosis, and NETosis. While the proposed research is rooted in my current postdoctoral work, it moves far beyond this foundation to better understand the molecular logic used by innate immune cells to choose between different cellular programs and how this relates to infection, autoimmunity, and neurological disease. Research: Neutrophils act as the first responders to viral, bacterial, or fungal infections and are important sentries of the innate immune system. Neutrophils must make complex decisions about when to migrate and when to stop and engage in antimicrobial effector response like phagocytosis and NETosis. How neutrophils assimilate information from their environment to decide between these different functional programs is not well understood. Recently, I discovered that two G-protein subunits (Gα12 and Gβ4) regulate neutrophil phagocytosis, migration, and NETosis by modulating plasma membrane homeostasis. My proposed studies will determine how plasma membrane composition and abundance control neutrophil and more generally professional phagocyte decision-making, both in the context of well-controlled in vitro assays and in animal models of infection and disease. My specific aims are to: 1) investigate the upstream and downstream effectors of Gα12 and Gβ4 in plasma membrane homeostatic regulation, 2) determine how plasma membrane abundance controls functional decision making by utilizing novel in vitro cell culture systems and a suite of in vivo mouse models I have created, and 3) determine how loss of Gβ4 and mis-regulation of plasma membrane abundance lead to aberrant phagocytosis of the myelin sheath on neurons in the context of Charcot Marie Tooth Disease, which is the most prevalent demyelination neuropathy of the peripheral nervous system. The fundamental principles elucidated from my studies could impact the development of novel immune based therapies to treat infections, cancers, autoimmune disorders, and neurological demyelination disorders. Environment: I am currently part of a unique environment where I interact daily with colleagues from the microbiology, immunology and cellular biophysics departments at both MSKCC and UCSF. These affiliations have provided a rich set of collaborative, technical, and scientific resources, and I hope to create a similar niche in my own independent lab and department/institute.
