We consist of trillions of interacting cells, but our understanding of how they work together is limited. This is because we have traditionally divided organisms from the top-down into broad cell types or iteratively-refined homogeneous subsets and then studied each such population separately. Yet recent studies have shown that even identical cells can exhibit functionally important differences and that cellular behaviors are strongly influenced by both the microenvironment and cellular interactions. Illustratively, for immune dendritic cells (DCs) and T cells - collectively responsible for recognizing pathogens and inducing adaptive immune responses - cellular subtype, signaling milieu, and physical contacts all impact the balance between proinflammatory and regulatory responses. Unfortunately, our inability to thoroughly measure and analyze each of these influences within the context of a complex system has limited our ability to grasp how proper immune function is achieved. I will leverage recent advances in nanotechnology and molecular biology to develop broadly applicable platforms for manipulating and profiling many interacting single cells so that I can uncover how they collectively perform systems-level behaviors from the bottom-up. These will include methods for culturing and monitoring cells in isolation and as a controlled ensemble, performing targeted manipulations, integrating different molecular measures (e.g., RNA and protein), and examining genomic RNA profiles in many single cells in-vitro and in-situ. Although broadly applicable, I will specifically utilize these technologies to examine how DCs and T cells synergistically fight pathogens and how T cells prevent uncontrolled DC inflammation that can drive autoimmunity. Collectively, my work will help identify the cellular players and the strategie they use to execute systems-level behaviors, will enhance our understanding of cellular response, communication, disease, and therapeutics, and will yield transformative new technologies for comprehensively and controllably profiling many different biological systems.
The goal of my proposed research is to develop five core, cross-disciplinary technologies to understand systems-level cellular behaviors from the `bottom-up,' using, as a model, innate immune dendritic cells and adaptive immune T cells, which are collectively responsible for recognizing pathogens and inducing adaptive immune responses. I expect that the proposed work will help transform the way in which we think about single cells, cell-cell interactions, diseased cellular states and therapeutics, providing a new paradigm for understanding the systems-level cellular behaviors manifest in multicellular organisms.
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