a systems-level analysis of cellular contractility
The broad objective of this proposal is to understand the molecular mechanisms that drive contractility of actin microfilaments in non-muscle cells. The actin cytoskeleton is an essential, dynamic scaffolding that defines cellular shape during directed cell migration, mitosis, and morphogenesis. In all of these processes, reorganization of the actin network is driven by contractile forces produced by a motor protein, non-muscle myosin II, and is governed by multiple regulatory factors including kinases, phosphatases, and small GTPases of the Rho superfamily. Aside from their roles in normal cell behavior, misregulation of the signaling pathways that control contractility may result in human diseases such as hypertension, inflammatory disorders, oncogenic transformation, and tumor metastasis. The conceptual framework underlying this proposal is that myosin-mediated contractile forces result from the interplay of numerous cellular components working in concert to define precise spatial and temporal patterns of myosin II activation. The specific aims for this proposal are designed to mount a comprehensive in vivo examination of cellular contractility in a model system: cultured Drosophila cell lines and the developing embryo. Drosophila is an ideal system for the proposed studies as it has a smaller genome and less functional redundancy than mammalian model systems. For example, flies possess a single gene for non-muscle myosin II, whereas the human genome encodes three. Despite its smaller size, the Drosophila genome encodes over 70% of the genes known to cause disease in humans. The use of, cultured cell lines will allow us to perform high-resolution light microscopy and RNAi-mediated gene inhibition, while the use of the organism gives us accestools and allows us to study gene function in a developmental context.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.