The ultimate goals of this COBREapplication are to increase the numbers of investigators in New Hampshire whoare competitive m securing NIH extramural funding, and to establish anImmunology and Inflammation Center that will be nationally recognized and freestanding in five years. Based on a highly interactive core of existingcollaborative and multidisciplinary faculty at Dartmouth Medical School (DMS)and Dartmouth Hitchcock Medical Center (DHMC), along with several key facultyat the University of New Hampshire (UNH) at Durham, the COBRE mechanism willprovide the resources to grow the Program in terms of both faculty developmentand the infrastructure necessary to attain functional center status. Facultygrowth will be facilitated by COBRE funding in four ways: 1) recruitment offive tenure-track faculty: two at the University of New Hampshire, and threeat DMS/DHMC; 2) mentored development of five promising junior investigatorsalready at Dartmouth, as the Project Leaders of the five Research . Projects;3) further linkage between DMS/DHMC and the UNH through Dr. Bruce Reinhold(Assistant Professor at UNH), a key co-Investigator who will provide massspectrometry expertise not available at DMS and DHMC; and also Drs. VernonReinhold (Project 3) and Thomas Pistole (Project 2) of UNH; and 4) synergisticscientific collaboration through the five research projects and associatedcores. Under the leadership of P.I. Dr. William R. Green, the currentDirector of the DMS/DHMC Immunology Program, together with substantiveinstitutional commitment by both DMS/DHMC and UNH, there is confidence thatthe strong existing base of investigators can be expanded and matured by theCOBRE mechanism to establish a Center, comprised of faculty who will besubstantially more competitive in obtaining extramural NIH funding, andthereby enhance the research grant portfolio of the State.The five individual research projects exhibit the multidisciplinary breadthcharacteristic of a center but also are intertwined by the common theme ofmodulation of immunity in various disease states, both at the level of non-specificinflammatory processes as well as with respect to specific adaptiveimmunity. Project 1 examines the central role of the cytokine tumor necrosisfactor alpha (TNF-a) in inflammatory processes and autoimmune disease, and theregulation of TNF-a production in T lymphocytes at the level of post-transcriptionalcontrol of mRNA stability. Project 2 studies the roles thatmacrophage activation and cytokines, in particular TGF-B1, play in theinflammatory processes involved in septic shock induced by lipopolysaccharidefrom Gram-negative bacteria, and in the liver inflammation observed in TGF-B1-deficient mice. In Project 3 biochemical and biophysical techniques areemployed to define the processing pathways of novel lipophilic antigens of M.tuberculosis for presentation by CD1, a monomorphic class 1B presentingmolecule, as the basis for vaccine development. Project 4 utilizes theapproach of CD64 targeting of antigen to professional antigen presenting cells(APC), overlayed with various strategies of APC activation, to amplify T cellresponses in human systems to prostate cancer related antigens. In Project 5augmentation of antigen loading and activation of dendritic cell (DC) APC formthe foundation for both preclinical studies and clinical trials to define DC-basedvaccines for colorectal cancer. Together these projects will contributeto defining creative new ways by which immune responses can be modulatedeither positively to combat tumors and bacterial infections, or in a down-regulatorymanner to lessen unwanted inflammation and autoimmunity.
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