This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Administrative Core Program Summary and Evaluation Overall Structure The Administrative Core has several missions, including overall organizational and scientific leadership, careful mentoring of the junior investigators, recruitment of new faculty, organizing of a seminar series in Immunology/Infectious Diseases, organizing COBRE retreats, and support of graduate students and postdoctoral fellows in COBRE laboratories. Progress on each of these areas is detailed below. Our current COBRE faculty include: Junior Faculty ?Beth D. Kirkpatrick, M.D. Vaccine studies of Denguevirus, poliovirus, and rotavirus ?Christopher Huston, M.D. Entamoeba Histolytica Phagocytosis and Inflammation. ?Jane Hill, Ph.D. Detection of aerosolized microbial products ?Jonathan Boyson, Ph.D. Function of SLAM locus in generation of NKT cells ?Jason Botten, Ph.D. (new faculty recruit) Immune response to arenaviruses and flaviviruses ?Matthew Wargo, Ph.D. (new faculty recruit) Phospholipase function in Pseudomonas aeruginosa during lung infection Senior Faculty ?Ralph C. Budd, M.D. - PI ?Gary Ward, Ph.D. ?Co-PI ?Elizabeth Bonney, M.D. ?Sally Huber, Ph.D. ?Mercedes Rincon, Ph.D. ?Cory Teuscher, Ph.D. ?Markus Thali, Ph.D. Core Facilties Faculty Advisors ?Proteomics and mass spec. ?Dwight Matthews, Ph.D. ?Microarray and Bioinformatics ?Jeffrey Bond, Ph.D. ?Administrative Core ?Ralph Budd, M.D. Of note is that the junior faculty contain two women and two physician/scientists. Furthermore, three of the infectious agents studied by the junior investigators in this proposal are either Category A (flavivirus) or Category B (Cryptosporidium parvum, Entamoeba histolytica) on the NIH/CDC list of Priority Pathogens. During the past year the second of three new junior faculty joined the COBRE, Dr. Matthew Wargo, who came from Dartmouth with strong expertise in the study of Pseudomonas aeruginosa during lung infection in cystic fibrosis patients. This will overlap strongly with studies of Dr. Jane Hill of our COBRE as well as efforts in the COBRE Vermont Lung Center. Our third and final new recruit, Dr.
Aim ee Shen, will arrive from Stanford in January, 2011. Dr. Shen is remaining at Stanford slightly longer as she received a K99 award in January, 2010, which obligates to remain at Stanford one more year. An additional area of development has been the new BSL3 facility, made possible with a COBRE supplement, as well as significant additional funds from the Dean's office of the College of Medicine. It will provide in vitro capacity, with plans for later BSL3 animal facility to be built adjacent to COBRE BSL3 in collaboration with the Vermont State Health Department (see below). Dr. Botten has need of an in vitro BSL3 facility for his work on arenaviruses, Dr. Beth Kirkpatrick may initiate a collaboration with a local company that wants to develop infrared detection of level 3 organisms. Dr. Matthew Wargo wants to expand his work on Pseudomonas to include the closely related agent, Burkholderia mallei. Dr. Jane Hill has interest in working on this organism as well. Interest from other COBRE and UVM investigators includes work with H5N1 influenza. At an organizational level, we continue our weekly joint laboratory meeting at which all COBRE investigators and their laboratory students/postdoctoral fellows present their work-in-progress. This brings together faculty from the disciplines of immunology, infectious diseases, microbial pathogenesis, plant defense, and bioengineering for a weekly venue at which to share our research. As director I have intentionally stressed the overlapping interests of the microbiologists and immunologists over common themes. The reason for this is not only the obvious realization that the immune system is present primarily to fight infection, but also that the most interesting and important breakthroughs in cell biology have almost always occurred at the interface between disciplines. From this initiative comes the very clear expectation that these collaborative interactions will result in collaborative R01s, and a new P01 Program Project Grant application. The areas of overlap have included the contributions of bacterial products in triggering Toll-like receptors (Borrelia burgdorferi triggering of TLR2, Drs. Budd and Teuscher;Coxsackievirus triggering of TLR3, Dr. Huber), NOD family members (Entamoeba triggering of caspase-mediated death of macrophages, Dr. Huston, and anthrax killing of macrophages via Nalp1b by Dr. Teuscher), CD1 triggering of NKT cells (Drs. Boyson and Bonney), and HIV, Borrelia and Cryptosporidium triggering of gamma/delta T cells (Drs. Thali, Budd, and Kirkpatrick). A closely related effort has been renewed interest in factors that influence immune memory, in anticipation of vaccine design as a logical outcome of our collaborative efforts. Specific signaling pathways in this area include the four histamine receptors (Dr. Teuscher's group has identified upregulation of H3R only on memory T cells), IL-6 promotion of IL-21, a B cell memory cytokine (Dr. Rincon), and caspase regulation of effector T cell survival (Dr. Budd). A third research theme that has begun to attract our attention is the possibility of autoimmune reactions as a result of the response to infectious agents. These have included the role of NKT cells in autoimmune hepatitis, given the co-localization of CD1d expression and resident NKT cells in the liver (Dr. Boyson), how dysregulated T cell homeostatic proliferation during pregnancy (Dr. Bonney) or in the absence of Fas (Dr. Budd) might augment autoimmune diatheses, and the influence on the number of CD4+CD25+ Treg by either Coxsackievirus infection (Dr. Huber) or day 3 thymectomy (Dr. Teuscher). In the spirit of fostering new interdisciplinary research efforts, we conducted our third COBRE retreat in March, 2009. This time, since faculty were quite familiar with individual lab research themes, and had already begun some collaborations, I elected to have that retreat centered around potential themes for P01 Program Project Grants. Four models were presented in the morning, each with its own leader. In the afternoon we broke up into groups to discuss details of how interested investigators might fit into a given theme. This has proved quite helpful and is now launching us toward one of our major goals of submitting collaborative R01 or P01 applications in the future. As a result of this retreat, we have also formed a research interest around the RNA sensor RIG-I helicases, as our group is studying many RNA viruses, including the arenaviruses, coxsackievirus, LCMV, and influenza. Our fourth COBRE retreat was held in January, 2010 to begin planning the COBRE renewal in September, 2010. This resulted in very valuable discussions of ways to increase collaboration through small pilot projects, begin to think about overlaps with other research themes at UVM, consider senior faculty recruits, and develop closer ties with the other COBREs at UVM and Dartmouth regarding core facility needs. As a result we launched a competition for collaborative pilot projects. Eight applications were received, reviewed by 4 external experts, and 3 were awarded one year of funding of $30,000. We plan to build more of this into the renewal application. As the Vermont Cancer Center (VCC) is undergoing a rebuilding process, there is a growing overlapping interest between our work on inflammation, the strong environmental carcinogenesis group at UVM, and the realization the same inflammatory pathways may link to tumorigenesis. We plan to work with the VCC in a senior faculty recruit in the area of inflammation-induced tumors. Most recently, the lung and immunology COBREs at UVM met with our counterparts at Dartmouth in a four-way """"""""COBRE Quadrille"""""""" to discuss more efficient sharing of core facility needs. This was a highly productive meeting. We have continued our COBRE seminar series in Immunology/Infectious Diseases. We have invited investigators who, for the most part, are studying the immune response to infectious agents. The list of speakers to date includes: Visiting Professors for Immunobiology Seminars -- 07/01/09 - 06/30/10 Name/Institution: Host: Date: Sylvie Guerder Mercedes Rincon 7/2/09 Centre de physiopathologie de Toulouse Purpon Dennis Metzger Ralph Budd 7/10/09 Albany Medical College Adolfo Garcia-Sastre Mercedes Rincon 8/14/09 Mount Sinai Victor Ambros Markus Thali 9/24/09 Umass-Worcester Douglas Weibel Jane Hill 10/9/09 Univ of Wisconsin-Madison Paul Stein Jon Boyson 10/30/09 Northwestern Univ. Erika Pearce Ralph Budd 11/20/09 Trudeau Institute Delisa Fairweather Sally Huber 12/11/09 Johns Hopkins Megan Shaw Markus Thali 1/8/10 Mount Sinai (NYC) Shane Crotty Ralph Budd 4/2/10 La Jolla Institute Makio Iwashima Sally Huber 4/16/10 Loyola University Art Arnold Sally Huber 4/23/10 UCLA Sebastian Joyce Jon Boyson 4/30/10 Vanderbilt Bartolomei Marisa Cory Teuscher 6/25/10 UPenn Evaluation We met with our External Advisory Committee (EAC) in October, 2009 for the third of our annual meetings with the EAC. The format for this retreat was the traditional presentation of each research project by the six junior investigators, the two core facilities, with an overview presentation by the director (Dr. Budd) and Co-Director (Dr. Ward). Our EAC members include Dr. Roger Davis (UMass), Dr. Eric Pamer (Sloan Kettering), Dr. William Petri (U. Virginia), and Dr. Donald Capre (former director of the Oklahoma Medical Research Foundation, and a former COBRE director). The review by our EAC is included. At the global level, their remarks included many laudatory comments regarding the synergism of the group, the importance of the theme, and the leadership. Two general recommendations were stressed. The first was seed money to be used to promote collaborative pilot projects, which we have now initiated. The second was to stress the need for the BSL3 facility. This has now also been resolved with the supplement and matching Dean's funds. New Faculty Recruitment We have now completed our target of recruiting three new faculty, in addition to the existing junior faculty. Dr. Jason Botten arrived from Scripps Research Institute on July 1, 2008. Dr. Botten is an expert in the study of arenaviruses (hantavirus, lassa virus, LCMV) and is mapping immunodominant epitopes of these viruses in humans for eventual vaccine design. Dr. Matthew Wargo came from Dartmouth and began at UVM in the fall of 2009. He will study pathogenicity of Pseudomonas. Finally, Dr.
Aim ee Shen will come from Stanford in January, 2011 and study Vibrio cholera toxin structure. Education In the area of education we have begun two initiatives. The first is a new graduate education concentration in Immunology/Microbiology as part of UVM's umbrella program in Cell and Molecular Biology. This is a direct result of the critical mass of investigators in this area that now exist at UVM, a direct result of the COBRE grant. As part of this initiative, we are developing a new curriculum for graduate students in this track. We started the first UVM-credited graduate seminar in advanced immunology two years ago and will continue that. In collaboration with the Vermont Lung Center COBRE, we offered joint seminar series in grant writing, laboratory management skills, and transgenic mice. Finally, we have continued to provide funding for two graduate students, Mr. Naresha Saligrama in Dr. Cory Teuscher's laboratory, and Lucas Tilley in Dr. Ward's group. Funds were also provided for three postdoctoral fellows, Dr. Andreas Koenig in Dr. Budd's laboratory, Dr. Dimitry Krementsov in Dr. Teuscher's laboratory, and Dr. Wei Liu in Dr. Huber's group. During the past year additional areas of accomplishment have been made in publications, including 23 from junior faculty and 47 from senior faculty. New grants in the past year by junior faculty include an R21 to Dr. Botten for work on arenavirus-host protein interactions, Dr. Kirkpatrick will likely become a co-PI on a Gates Foundation grant with Dr. William Petri at UVA to study poliovirus and rotavirus vaccine efficacy. Dr. Matt Wargo received a very favorable score on a K24 application that may be funded.
Aim ee Shen was funded for her K99 grant. Among senior faculty, Drs. Budd, Huber, Rincon, and Teuscher had their P01 Program Project Grant renewed. It is now in its 12th year. Other accomplishments include the completion in June 2009 of Dr. Budd's tenure as Chair of the NIH study section, """"""""Immunity and Host Defense"""""""", and also serving as Chair of a study section in March, 2011 to review U19 vaccine grants. He was also a UVM University Scholar for 2009-2010. Dr. Teuscher became a member of the NIH study section """"""""Clinical Neuroimmunology and Brain Tumor"""""""". As a result of all these combined efforts, the Vermont Center for Immunology and Infectious Diseases has been recognized as a center of excellence in the College of Medicine by Dean, Dr. Frederick Morin. Thus, we have come a remarkable long way since the inception of the Immunobiology Program 14 years ago with one founding member. Summary of continuing accomplishments during the current funding period ?Continuation of joint weekly laboratory meetings ?Biweekly seminar series of outside speakers ?Offering of new courses in advanced immunology, grant writing skills, laboratory management skills, and transgenic mice ?Recruitment of the third of three new faculty to the center ?Bridging to members of the Vermont Lung Center COBRE team (Drs. Charles Irvin, Matt Poynter and Laurie Whitacker) and with the Immunology and Lung COBREs at nearby Dartmouth Medical School (Drs. William Green and Bruce Stanton, PIs) ?Subcontract award for NIH-funded dengue vaccine trial by Dr. Kirkpatrick, as well as likely receipt of a Gates Foundation grant to study poliovirus and rotavirus vaccines. ?Receipt of an R21 grant by Dr. Jason Botten ?Receipt of a K99 award by Dr.
Aim ee Shen ?A successful 4th retreat centered around formulating themes for one or more Program Project Grants Future Directions During the fifth year of funding, we will concentrate on : ?initiating the collaborations through the pilot project program ?Construction of the BSL3 facility ?Plan for the COBRE renewal application
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