2010 — 2013 |
Fehon, Richard G [⬀] Mcclatchey, Andrea I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Analysis of Erm Proteins in Epithelial Morphogenesis
DESCRIPTION (provided by applicant): The ability to form specialized membrane domains composed of unique sets of transmembrane proteins, associated cytoplasmic proteins, and phospholipids, is a fundamental property of polarized epithelial cells. Membrane domains, such as the apical surface or junctional complex, allow spatial segregation of functions at the plasma membrane that are essential for polarized epithelia. Central to this process is the formation of protein complexes on the cytoplasmic side of the membrane that localize transmembrane proteins, regulate their signaling output and control their abundance via regulated endocytosis. The Ezrin, Radixin, Moesin (ERM) proteins organize a key role in this process. In this proposal we describe experiments designed to take advantage of the combined expertise of two investigators, Andrea McClatchey (Harvard/MGH) and Richard Fehon (University of Chicago), to extend our understanding of ERM function. The investigators and their laboratories bring together expertise in two powerful experimental systems, the mouse and Drosophila. The proposed research utilizes a multifaceted approach, including genetics, biochemistry, cell biology and proteomics to better understand the functions of these highly conserved proteins. Specifically, we plan to: 1) Determine the molecular mechanisms that link the ERM proteins to the activation state of Rho in developing epithelial cells. 2) Examine the molecular mechanisms that regulate ERM activity, particularly in the context of how ERM activity is dynamically regulated. 3) Delineate the function of the ERM proteins in cell:cell junction remodeling. 4) To build an integrated model of ERM-mediated complex formation. These experiments are expected to provide novel insight into the functions of ERM proteins in biological processes such as apical-basal polarity cytoskeletal regulation, intestinal lumen formation and homeostasis, and metastasis. They should also yield a better understanding of the cellular processes that establish specialized membrane domains in polarized cells, and inform our understanding of cytoskeletal and junctional dynamics during morphogenesis and in disease. PUBLIC HEALTH RELEVANCE: We will carry out complementary and synergistic studies in two powerful model systems - Drosophila and the mouse - to examine the function of ERM proteins in epithelial morphogenesis. Specifically, we will test the hypothesis that ERM proteins provide local regulation of RhoGTPase activity in response to upstream signals/receptors using molecular tools and genetic models that we have developed in each system. We will also delineate the function of ERM proteins in cell junction remodeling/stability as suggested by the phenotypes of ERM loss in both flies and mammals.
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0.957 |
2012 — 2016 |
Mcclatchey, Andrea I |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cancer Cell Biology @ Dana-Farber Cancer Inst
PROJECT SUMMARY (See instructions): The Cancer Cell Biology Program seeks to enable new approaches to cancer pathogenesis and therapy by catalyzing interactions between DF/HCC scientists and clinicians. The overarching goal is to facilitate bench-to-bedside collaborations, bringing basic discoveries into the clinic, and bedside-to-bench collaborations, when a deep knowledge of the clinical features of a particular disease helps drive fundamental discovery of pathogenesis mechanisms, ultimately leading to new treatment strategies. The specific aims of the Cancer Cell Biology Program are to: 1) exploit emerging technologies to elucidate the cellular mechanisms that underlie tumorigenesis; and 2) leverage basic science discoveries to inspire pre-clinical and clinical development of novel therapeutics. The 99 members of this Program are unified through their use of molecular, biochemical, and cell biological approaches to delineate and alter cancer cell behavior. They represent all DF/HCC institutions. In 2009, members received more than a total of $79.3 million in overall grant funding (TC), of which $22.1 million was from NCI and $42.5 million was from other peer-review sponsors. Members published 1,546 publications during the current project period (2006 to 2010), of which 5% were intra-programmatic, 26% were inter-programmatic, and 20% were inter-institutional. Inter- and intra-programmatic collaborations have not only led to the development of novel therapeutics, but have also inspired complementary avenues of basic scientific investigation. In the 2005 CCSG renewal, the program received an outstanding merit score. It is poised to continue that trajectory in the next project period.
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0.909 |