Cressida Madigan - US grants

DESCRIPTION (provided by applicant): This proposal examines the role of the pro-resolving lipid mediators, resolvins, protectins, and maresins, in mycobacterial pathogenesis. These recently discovered lipids effectively combat sterile inflammation, but their role in infection-induced inflammation remains largely unexplored. Such an exploration seems particularly warranted for TB, which is increasingly recognized as a disease of excess as well as failed inflammation. Indeed, the use of the zebrafish has revealed a dual role for lipoxins in TB: pathogenic in excess, yet restoring resistance when administered pharmacologically in the setting of excess inflammation. Importantly, key aspects of these zebrafish findings have been validated in humans and should enter the clinical arena before long. It is very likely that the other pro-resolving mediators will play complex roles in TB that offer important therapeutic approaches. Thus, completion of these Aims will not only contribute to our understanding of how immunopathology is interwoven with mycobacterial pathogenesis, but also potentially suggest new treatments for diseases with an immunopathology component.

Rapid advances in the forward engineering of complex gene circuits in living cells has established the transformative potential of synthetic biology for uncovering the rules of life and controlling biotechnological processes. This project aims to harness and further develop the ability of different strains and species of bacteria to communicate and respond synchronously to changing environments. Our multi-disciplinary approach combines advances in genetic engineering, microfluidic technologies, and computational methods to design novel gene networks that can orchestrate bacterial population dynamics in the complex environment using relevant environmental cues.

The overall goal of this project is to model, engineer, and characterize bacterial circuit dynamics in the complex environments. Two new bacterial gene circuit systems will be designed. The first is a long-range coupling platform for synchronizing colony behavior through hydrogen peroxide. The second is a system of lysis-mediated gene circuits that can be used to regulate the co-culture of multi- strain ecologies. The investigators will develop computational modeling and quantitative measurement technology that will lead to both informed development and quantitative characterization of newly engineered circuits in spheroid environments derived from animal tumors. Using this knowledge, the researchers will combine developed circuits with therapeutic delivery or biosensing strains to create relevant and functional synthetic systems for application to complex environments. An Elementary School Science Partnership program, which was initiated in 2011 with NSF support, will be expanded. The program currently serves two Title I elementary schools in the San Diego area, Ocean Knoll and Lafayette, and includes the District?s Deaf and Hard of Hearing program. The program is led and run by UC San Diego students under supervision from the investigators. This project will provide ample opportunities for cross-disciplinary training of the next generation of quantitative biologists. In a broader context, it will bridge the methodological gap between the study of bacteria in a lab setting and their deployment in complex real-world environments.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.