Welcome to the Perrimon Lab at Harvard Medical School!
We are using Drosophila as a model system to characterize the responses of specific cells to extracellular signals. Previous work from our laboratory has focused on the characterization of the signaling pathways that orchestrate embryonic patterning and morphogenesis. More recently however, as we now have a rather good knowledge of these processes, we have become more interested in studying: 1. the mechanisms involved in the control of cell and tissue growth, and especially the roles of the Insulin pathway in these processes; and 2. how signaling mechanisms are used in the context of homeostasis. ‘Homeostasis’, from the Greek words for ‘same’ and ‘steady’, refers to ways in which the body acts to maintain a stable internal environment despite perturbations. We are interested in two kinds of homeostasis: 1. Tissue Regeneration that addresses the maintenance of tissue integrity by stem cell systems, as is the case of the gut that exhibits slow regeneration under normal conditions but accelerated regeneration when injured, and 2. Physiological Homeostasis that encompasses the mechanisms by which differentiated tissues, such as muscles, grow, maintain their mass, and communicate with others to maintain physiological and growth homeostasis of the organism. We are studying these fundamental problems in Drosophila because the fly is one of the prime model systems for studying the basis of human diseases and, arguably, has an unmatched arsenal of tools for both in vivo and in vitro functional genomic studies.
Ongoing work in our laboratory can be subdivided into four categories. First, to facilitate Functional Genomic approaches in Drosophila, we develop, improve, and generate reagent resources to make the process of gene discovery and identify genes’ function both in vitro/tissue culture and in vivo faster, easier, more reliable, and genome-wide. Importantly, to maintain and build on the Drosophila community’s tradition of sharing, which was pivotal to establish Drosophila as one of the premier model systems, we make the methods and reagents that we develop immediately available to the community. In 2003 we created the Drosophila RNAi Screening Center (DRSC;http://www.flyrnai.org/) at Harvard Medical School for cell-based genome wide RNAi screens to make this technology available to the community. In addition, we developed new shRNA vectors for in vivo RNAi and in 2008 established the Transgenic RNAi Project (TRiP; http://www.flyrnai.org/TRiP-HOME.html) to build a genome scale resource of transgenic shRNA flies. Second, we apply these tools to tissue culture cells to elucidate the organization of the core Cell Circuitry networks involved in signaling. Our approach, based on genome-wide RNAi screening, proteomic and computational analyses, is to identify the parts responsible for the reception and integration of the signals, organize them into pathways and networks, and then validate the findings in more complex in vivo biological systems; i.e., muscles and gut stem cells. Third, as a model for Tissue Regeneration, we study the mechanisms that control the proliferation of Drosophila adult gut stem cells in both normal and injured conditions. Fourth, as a model for Physiological Homeostasis, we study Drosophila muscles to identify the molecular mechanisms involved in their growth, maintenance, and aging. These studies have led us to recognize the critical role of muscles in particular in regulating homeostasis of other tissues. To expand on these observations, we are now taking a more systematic approach to identify molecules involved in organ communication that influence metabolism and aging.