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February 19, 1999 Seed Grants Nurture Collaborative Research The HMS/Affiliated Hospital Collaborative Seed Grant Program, a new effort to encourage collaboration between Quad- and hospital-based scientists, announced the five winners of its first round of grants, effective January 1. These seed grants, funded jointly by HMS and the participating hospitals, are expected to attract increased NIH funding for projects that show promise of further development. The winners are: Ann Hochschild, associate professor of microbiology and molecular genetics at HMS, with Michael Greenberg, professor of neurology at Children's, for an E. coli-based assay to study protein-protein interaction; Peter Howley, George Fabyan professor of comparative pathology, and Frank McKeon, professor of cell biology, both at HMS, with Christopher Crum, professor of pathology, and Arlene Sharpe, associate professor of pathology, both at Brigham and Women's, for a study of the p63 gene, a homolog of p53, in epithelial cell maturation and oncogenesis; Catherine Lee, associate professor of microbiology and molecular genetics at HMS, with Beth McCormick, instructor in pediatrics at Massachusetts General, for studies on the induction of IL-8 secretion from intestinal epithelial cells by Salmonella; Philip Leder, John Emory Andrus professor of genetics, with Michael Yaffe, instructor in surgery at Beth Israel Deaconess, for a study of the structure and function of WW domains as therapeutic targets for neurodegenerative diseases and birth defects; and David Knipe, Higgins professor of microbiology and molecular genetics at HMS, with Robert Finberg, professor of medicine at the Dana-Farber Cancer Institute, for the development of prostate cancer vaccines. Hochschild and colleagues recently developed an E. coli-based genetic assay for detecting protein-protein interactions, while Greenberg has a longstanding research effort directed at elucidating signal transduction mechanisms that regulate neuronal differentiation and survival. The two investigators plan to use their seed grant to validate the use of the assay system in studying medically relevant protein-protein interactions that play important roles in cellular signaling pathways. "Disruption of these critical signal transduction pathways has been implicated in a variety of devastating diseases including cancer and neurodegenerative disorders," they write. "Therefore the discovery of small molecule therapeutics that either perturb or potentiate these protein-protein interactions has become an important goal ... these assays may in the future provide a rapid and convenient way to screen for potential therapeutics." The recently discovered gene p63 is strikingly similar in its DNA sequence to p53, a major tumor suppressor gene. Although p63's cellular functions are unknown, the gene has been found to be highly expressed in a number of cancer-prone tissues such as skin, prostate, and breast, and to bind to the same DNA regulatory sites as p53. These findings suggest that the two genes might functionally interact in some way to influence cell growth control. Crum, Sharpe, Howley, and McKeon will use a multidisciplinary approach to deciphering p63's normal functions and its possible roles in tumorigenesis. The group will perform a functional analysis of p63 using transgenic and knockout mouse technologies. McCormick and Lee will examine the ability of different serotypes of the bacteria Salmonella to induce secretion of the signaling molecule interleukin-8 (IL-8) from intestinal epithelial cells, and attempt to identify bacterial factors that modulate this secretion. Previous studies on one type, S. typhimurium, have suggested that IL-8 governs the movement of neutrophils out of blood vessels and across the intestinal epithelium, a hallmark of gastroenteritis. "The ability of Salmonella to induce IL-8 secretion may be an important determinant of bacterial virulence and host/disease specificity," they write. "Our studies should also provide insight into the pathophysiology of inflammatory bowel diseases." WW domains are one type of modular signaling domain found within proteins--short stretches of amino acids that have come to be recognized as the key regions through which proteins transmit information to one another. "These modular signaling domains form a molecular alphabet in which the syntax of cell signaling is written," Yaffe and Leder write. "Developing a detailed understanding of the 'grammatical rules' by which these domains function and communicate with each other is certain to have broad biomedical applications." The domains (named for their hallmark double tryptophan--W is the single letter code for this amino acid) have been identified in more than 50 proteins, including some involved in diseases ranging from Alzheimer's to hypertension to HIV infection, but are still poorly understood. Yaffe and Leder's seed grant will expand their existing collaboration, using biochemistry, genetics, and structural biology to measure the affinity of WW domains to different peptides and preliminary protein targets, and to discover new physiological targets for WW domains. In their work toward a prostate cancer vaccine, Knipe and Finberg will test whether herpes simplex virus can serve as a vaccine vector to express tumor antigens and thereby immunize mice against tumor cell challenge, and whether mutant HSV strains expressing prostate-specific antigens can expand tumor-specific human T cells. "Vaccines could work either by themselves stimulating immunity to the targeted antigen, or by allowing for in vitro expansion of T cells which could then be infused into patients," they explain. --Tom Reynolds