The goal of my lab is to engineer synthetic receptors and signaling adaptors that control immune cell behaviors such as survival, proliferation, differentiation, migration, and cell-mediated cytotoxicity. Synthetic receptors are highly modular systems that are critically important as emerging cell therapies and synthetic biology-based research tools. For example: chimeric antigen receptors (CARs) are powerful therapeutics for blood cancers. Currently, we are able to slowly and painstakingly construct these synthetic receptors through iterative design, but we lack the necessary tools to rationally engineer receptors that produce desired behaviors in mammalian cells. My laboratory will experimentally screen libraries of hundreds to thousands of receptors and use machine learning approaches to discover design rules that enable rational design of modular receptors with predicted cellular functions. Ultimately, this work will improve our understanding of modular biological systems and enable rapid development of more effective cell therapies. Through collaborations and as my research expands, I expect that we will engineer receptors useful for modulating many processes in diverse cell types.
Many signaling molecules contain modular peptide signaling motifs with complementarity to various effector proteins such as kinases, phosphatases, phospholipases, and other effectors. For example, the pYMFM peptide motif binds the kinase PI3K and the ITpYAAV peptide motif binds the phosphatase SHP-1. Various combinations and arrangements of signaling motifs produce a wide variety of signaling and cell phenotypes. Despite the modularity and complementarity inherent to receptor signaling, facile receptor engineering eludes us because we lack predictive models relating signaling motif combinations to cell phenotype. A major goal of this work is to develop quantitative models and learn design rules that allow us to harness the modularity and complementarity of receptor signaling to predictably engineer receptors that control cell phenotypes. A number of the proteins involved in immune cell function are multivalent, containing numerous src-homology 2 (SH2) domains or src-homology 3 (SH3) domains, as well as peptide motifs that bind to such domains. These proteins include PLCg1 and Grb2, important cell signaling effector molecules that have been observed to induce phase separation. Another such protein, Vav1, is critical for initiating cytoskeletal rearrangements upon immune cell activation. The lab will build synthetic signaling molecules that contain novel combinations and arrangements of the the SH2 domains and peptide motifs involved in T cell activation. We will use imaging techniques observe phase separation (by TIRF) during immune cell signal and subsequent cytoskeletal rearrangements (by super-resolution microscopy) to understand how synthetic and natural signaling molecules mediate these processes and ultimately influence the resulting cell phenotypes.
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