Laura Segatori develops innovative, system-level strategies based on the integration of synthetic biology, protein engineering, and bionanotechnology to reprogram the cellular quality control system in mammalian cells. The approaches allow for a broader understanding and control over the molecular mechanisms that regulate protein processing for applications ranging from development of cell-based therapies to the production of biologics.
For nearly two decades, Segatori’s research efforts have focused on understanding and characterizing the elaborate molecular and cellular pathways that cope with protein misfolding. To this end, the Segatori group combines experimental approaches and predictive modeling to create genetic circuits that perturb and reprogram innate cellular pathways that mediate protein processing and promote degradation and recycling of aberrant cellular components.
Significant research has involved the development of protein engineering toolkits designed to unlock, probe, and manipulate the chaperone and degradation processes. Knowledge from these studies has led to more recent efforts focused on engineering nanoparticles to serve as a delivery systems and nanotherapeutics to enhance the clearance of toxic materials that accumulate in association with the development of a range of human diseases. The therapeutic strategies are validated using the group’s in vitro model systems of loss of function and gain of function diseases.
Segatori’s research has led to 36 peer-reviewed journal publications, two patents and three patent applications. She has been awarded numerous competitive National Science Foundation (NSF) and National Institutes of Health (NIH) grants, including an NSF CAREER Award (2013) to engineer cellular clearance pathways using nanoparticles, and several Hamill Innovation Awards (2009, 2011, 2013, 2014, 2015, 2017), and a Medical Innovation Award (2010) from Rice’s Institute of Biosciences and Bioengineering.
Ongoing work in her lab is supported by the Welch Foundation; the Kleberg Foundation; the Chemical, Bioengineering, Environmental and Transport Systems (CBET) division and the Molecular and Cellular Biosciences (MCB) division of the NSF.
Cells physiologic states are dictated by the collective behavior of thousands of molecular components and may vary dramatically depending on environmental factors, resulting in non-linear behaviors. Despite significant advances in systems and synthetic biology, protein function in cells remains hard to decipher due to the plasticity and adaptability of cellular regulatory and quality control mechanisms. Researchers in the Segatori group explore innovative protein engineering approaches to regulate protein degradation, thereby controlling protein steady state levels in mammalian cells with high specificity and selectivity.
Protein biosynthetic needs and secretory demands in mammalian cells are constantly integrated and coordinated through a complex quality control system that regulates the rates of protein synthesis, folding, and trafficking. Accumulation of aberrant (misfolded) proteins triggers activation of a series of signaling cascades (stress response) aimed at relieving proteotoxic stress and restoring homeostasis or executing apoptosis to eliminate irremediably damaged cells. The Segatori group designs orthogonal genetic circuits that interface with the cellular stress response through sophisticated feedback mechanisms to control cellular fate upon proteotoxic stress. Applications of these studies range from the development of strategies to enhance production of biologics to the design of cell-based therapies.
Engineered nanomaterials (ENM) exert a diverse array of effects on biological systems, paralleling the heterogeneous and complex properties of engineered nanomaterials themselves. Yet all these effects, whether tissue degeneration, inflammatory responses, or carcinogenicity, are ultimately a consequence of the interaction between nanomaterials and cellular components that also operate at the nanoscale. In particular, the autophagy-lysosome system is activated in response to a variety of nanosized materials that are encountered by the cell and is at the forefront of the cellular response to the uptake of engineered nanomaterials. As the main cellular catabolic pathway, the autophagy-lysosome system plays a vital role in maintaining cellular homeostasis and survival, and defects in this degradation system may have deleterious effects on cells, possibly leading to pathologic conditions. The autophagy-lysosome system ultimately shapes nanomaterial-invoked changes in cellular and organismal physiology: any outcome of the nanomaterial-cell interaction, whether desirable or adverse, is in fact the result of either nanomaterial-induced alterations of the autophagy-lysosome system, or of the interaction of nanomaterials with other cellular components after the ENMs are processed by the autophagy-lysosome system. Research in the Segatori lab aims at elucidating the design rules of next-generation nanomaterials with autophagy-modulating properties with the dual goal to further our fundamental understanding of the response of the autophagy-lysosome system to nanosized structures and particles, and to develop nanotherapeutics for the treatment of human diseases.