$38 million glue grant to explore cell migration

BETHESDA — Directed cell movement is vital for several key processes necessary to maintain life and health. Without it, tissues and organs would not form correctly, wounds would not heal and leukocytes would be unable to track down invading viruses and bacteria to fight infection. Cell migration also plays an important role in various disease states, facilitating tumor metastasis, contributing to inflammation, and altering histogenesis to cause congenital brain defects.Recognizing the need for an integrative, interdisciplinary approach to promote the understanding of cell movement, the US National Institute of General Medical Sciences (NIGMS) has awarded a five-year, $38 million 'glue grant' to a consortium of scientists comprised of researchers from 12 universities and research institutions in the United States, as well as the University of Oxford and the Technische Universität, Berlin. "We have identified what we consider to be barriers to progress" — aspects of the field that are too complex to be explored by single investigators — explained Alan Horwitz, principal investigator of the Cell Migration Consortium (CMC) project and Professor of Cell Biology at the University of Virginia School of Medicine. "We are taking problems that are not easily tackled by one person and we are putting together interdisciplinary teams to answer them."The project aims to bring together researchers from a variety of disciplines through collaborative research projects, meetings (including an annual cell migration meeting), and web-based interactive activities. It will include biologists, chemists, biophysicists, optical physicists, mathematicians, computer scientists, geneticists, and engineers, working in an interactive environment funded by a grant of $8 million in the first year.This discipline "is ready to move to the next level," argued J. Thomas Parsons, co-principal investigator and Professor and Chairman of Microbiology at the University of Virginia. It requires a "diversity of expertise," and the glue grant "will really help push the effort ahead."The ultimate goal of the project, according to Horwitz, is to develop a mathematical model of cell migration. "We are not proposing to test hypotheses. We are proposing to develop reagents (both animal and chemical), to accumulate information, and to support the research community by providing full access to the information, reagents, and technology generated," he explained. Data and operational information will be presented on the consortium's website.The consortium will focus its activities on several multi-investigator initiatives: • Structure — to determine the molecular structure of the multi-protein assemblies that drive cell migration. • Protein discovery — to identify and catalogue the complement of proteins that regulate and take part in cell movement — 'the migration proteome' — and to characterize their interactions and modifications. • Signaling — to develop probes for locating and quantifying the signals that control migration. • Modeling — to develop mathematical models of cell migration. • Transgenic and knockout mice — to generate novel mouse models and derive cell lines to study directed cell movement. • Imaging — to develop new imaging technologies to study cell migration in vivo. • Reagents — to produce new substrates to use in studies of cell movement.Cell migration has proved to be a particular difficult puzzle to solve, primarily because of the complexity of the spatial and temporal coordination of molecular and cellular processes that enable a cell to move. The front of the cell is doing one thing, forming attachments and protruding, while the rear of the cell is doing something else, releasing attachments and retracting. At the same time, the middle of the cell is translocating.Although each of these cellular processes is the subject of intensive investigation in various laboratories, each is usually studied as a separate entity, and not as one part of a series of coordinated operations that are regulated by extracellular cues, intracellular signaling pathways and dynamic cellular systems. The CMC intends to operate as a coordinated, interactive body, with the shared goal of understanding, visualizing, and modeling the integration and regulation of these complex processes.The structural component of the project has two main objectives: to use low resolution techniques such as X-ray and nuclear magnetic resonance imaging to characterize the structures of the cytoskeletal and signaling proteins and protein complexes involved in cell migration; and to apply high resolution imaging technology, including cryo-electron microscopy and tomography to determine how these components are assembled into the supermolecular organelles that drive cell movement.The signaling initiative will focus on the development of assays and reagents to identify and characterize adhesion signaling pathways. The ultimate goal of this component of the project is to produce "quantitative assays of signaling in live cells as they walk," said Horwitz. Current assay techniques that measure the level of expression of a protein in a cell have limited value in the analysis of signaling pathways involved in cell movement. During cell migration, the total levels of proteins in a particular signaling pathway may not change very much in a whole cell or in a population of cells, but they may change at various sites within the cell. What are needed are assays that can detect localized changes in protein expression. "Maybe something is activated at the front of the cell and inactivated at the rear of the cell," hypothesized Martin Schwartz, a core investigator in the consortium and Professor in the Department of Vascular Biology at Scripps Research Institute. This type of analysis will require probes — antibodies and fluorescent probes — that can be imaged and can detect activated states of key signaling molecules. "When interesting molecules are identified and their structures determine, we can then use that information to develop probes," said Schwartz. "We do not understand how to interpret signaling in the context of what the structure looks like," added Parsons. One goal of the glue grant is to generate integrative information that will make it easier "for the structure people to target a problem that the signalers feel is ripe to identify."The purpose of the consortium — to understand directed cell movement — has potential applications in a variety of therapeutic areas, one of the most obvious being tumor metastasis. The ability to block or control cell movement could have profound implications for the field of cancer therapeutics, as tumor spread is the cause of most cancer deaths. Cell migration is also an intrinsic part of tumor formation and is required for vascularization.Controlling leukocyte migration could offer an effective strategy for treating inflammatory disease. In addition, cell movement plays a role in osteoporosis, as osteoclasts need to move about to absorb bone. Other clinical applications of cell migration research could include stem cell transplantation and the production of replacement tissues and organs, both of which are dependent on controlled morphogenesis and cell movement.While the glue grant will accelerate research on cell movement, much of the data, techniques, and reagents generated by the consortium will be relevant to other areas of basic research as well. The project should make available valuable resources, including transgenic mouse models, and will generate a variety of new therapeutic targets for drug discovery.

$38 million glue grant to explore cell migration

An international consortium of scientists from a number of disciplines have been brought together to investigate how cells move.

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