Research

How are molecular and mechanical signals translated across time and length scales to organize and drive the collective behaviors that maintain and shape human tissues?
Our lab broadly investigates how biochemical and mechanical signals are coordinated across biological scales (molecules to cells to tissues) to maintain normal tissue structure or drive pathology. Our efforts are primarily focused in the experimental arenas of cardiovascular disease and solid tumors.
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At the molecular level, we are experts in elucidating new mechanisms underlying adhesion biology, the interactions of cells with their neighbors and their microenvironment. We study how core adhesion molecules such as cadherins and integrins integrate and orchestrate chemical and mechano-signaling to specify multicellular behavior, proper organization and differentiation of complex tissues, as well as facilitate the progression of disease.
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At the cellular level, we develop and apply quantitative imaging and molecular tools (optogenetics, synthetic biology) that allow us to measure, direct, and perturb cellular behaviors to understand how collective decisions initiate and propagate within tissues. 

At the tissue level, we engineer organotypic 3D microfluidic models of human tissues with defined architectures and microenvironments in vitro that permit the simulation, molecular dissection, and quantitative analysis of in vivo-like morphogenic processes. We are working to combine these platforms with organoid systems, unbiased proteomics, and single-cell analyses to build spatio-temporal road maps of human development and disease.
Cell Adhesion regulation of cell and tissue morphodynamics
Cell-cell contacts serve to establish adhesive connections that transmit mechanical forces between cells, yet also critically regulate the localization, duration, and cytoskeletal coupling of receptor interactions governing biochemical juxtracrine signaling. This regulation occurs through ordered domains at cell-cell interfaces that are organized by molecular interactions within with the plasma membrane as well as associations with the underlying cytoskeleton of the cell cortex. This integration of cell surface receptors with the cortical cytoskeleton forms a critical nexus of instructive morphogenic information. However, our understanding of this interplay is nascent, particularly when defining contextual relevance during complex three-dimensional (3D) tissue morphogenic events. 
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Using proximity-ligation mass spectrometry, we have identified a host of candidate proteins controlling spatial order of signal receptors, mechanotransduction, and downstream growth/fate signaling at cell-cell contacts. We are evaluating the morphogenic significance of these interactions in our engineered tissue systems, as well as using these insights to inform biomaterials design that mimic cell-cell adhesion for 3D tissue patterning and regeneration.
Activation and Function of Notch receptors
Our recent work has uncovered a novel signaling mechanism for Notch receptors, termed ‘cortical signaling’, in which activation of the receptor leads to adhesion and cytoskeletal rearrangements through protein-protein interactions at cell-cell adherens junctions (AJs) and remodeling of cortical actin networks (Polacheck and Kutys+, Nature, 2017). Contrasting developmental processes, many cell types are characterized by baseline ‘homeostatic’ Notch signaling, which is a mode of regulated cell-cell adhesion and tissue integrity absent a robust Notch transcriptional response  This has led to a deeper appreciation of not only the morphogenic consequences of Notch receptor activation but has also indicated precise regulation of receptor activity by distinct cell compartments at cell-cell interfaces and the cortical cytoskeleton that have gone unappreciated. ​Current efforts are focused on dissecting the reciprocal nature of cytoskeleton/adhesion - Notch receptor interactions, their role in controlling multicellular communication and mechanobiology, and defining significance in the context of tumor suppression and vascular biology.
Building Cellular and mOlecular Road Maps of DEvelopment and Disease
How emergent collective behaviors arise within a tissue is poorly understood. In the context of cancer, recurring human mutations have been identified but how they contribute to the morphogenic behaviors that underlie tumor progression is not known. Similarly The tissue-scale morphodynamics that shape developing and regenerating organs are orchestrated by heterogeneous cell populations with precise spatial and temporal control. With the booming advent of stem-cell derived organoid systems that provides an avenue towards in vivo organ complexity, we are working to engineer new microphysiological systems that provide architecture and reproducibility to organoid systems and permit the controlled induction of 3D tissue morphogenic behaviors, such as branching morphogenesis. It is our goal to combine such platforms with unbiased molecular technologies to build a mechanistic molecular and cellular road map of development and disease in complex human tissues ex vivo.
Next Gen Human Biomimetic Models for biological discovery 
 A major hurdle in the scaling of organoid systems in vitro and in the development of tissue engineered therapies for regenerative medicine is the incorporation of stable vasculature. The vasculature not only systemically provides nutrients and removes wastes from tissues, but through 'angiocrine niches' actively signals to resident parenchymal and stromal cells to promote tissue maturity and homeostasis in an organ-specific manner. We are leveraging our fundamental cell biological discoveries to build next generation microfluidic tissue models that permit for investigation into these heterotypic juxtracrine interactions and paracrine signaling.