COBRE: DMS: MICROVILLAR STRUCTURE AND FUNCTION ON CIRCULATING LYMPHOCYTES

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DESCRIPTION (provided by applicant): The ultimate goals of this COBRE application are to increase the numbers of investigators in New Hampshire who are competitive m securing NIH extramural funding, and to establish an Immunology and Inflammation Center that will be nationally recognized and free standing in five years. Based on a highly interactive core of existing collaborative and multidisciplinary faculty at Dartmouth Medical School (DMS) and Dartmouth Hitchcock Medical Center (DHMC), along with several key faculty at the University of New Hampshire (UNH) at Durham, the COBRE mechanism will provide the resources to grow the Program in terms of both faculty development and the infrastructure necessary to attain functional center status. Faculty growth will be facilitated by COBRE funding in four ways: 1) recruitment of five tenure-track faculty: two at the University of New Hampshire, and three at DMS/DHMC; 2) mentored development of five promising junior investigators already 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 mass spectrometry expertise not available at DMS and DHMC; and also Drs. Vernon Reinhold (Project 3) and Thomas Pistole (Project 2) of UNH; and 4) synergistic scientific collaboration through the five research projects and associated cores. Under the leadership of P.I. Dr. William R. Green, the current Director of the DMS/DHMC Immunology Program, together with substantive institutional commitment by both DMS/DHMC and UNH, there is confidence that the strong existing base of investigators can be expanded and matured by the COBRE mechanism to establish a Center, comprised of faculty who will be substantially more competitive in obtaining extramural NIH funding, and thereby enhance the research grant portfolio of the State. The five individual research projects exhibit the multidisciplinary breadth characteristic of a center but also are intertwined by the common theme of modulation of immunity in various disease states, both at the level of non-specific inflammatory processes as well as with respect to specific adaptive immunity. Project 1 examines the central role of the cytokine tumor necrosis factor alpha (TNF-a) in inflammatory processes and autoimmune disease, and the regulation of TNF-a production in T lymphocytes at the level of post-transcriptional control of mRNA stability. Project 2 studies the roles that macrophage activation and cytokines, in particular TGF-B1, play in the inflammatory processes involved in septic shock induced by lipopolysaccharide from Gram-negative bacteria, and in the liver inflammation observed in TGF-B1- deficient mice. In Project 3 biochemical and biophysical techniques are employed to define the processing pathways of novel lipophilic antigens of M. tuberculosis for presentation by CD1, a monomorphic class 1B presenting molecule, as the basis for vaccine development. Project 4 utilizes the approach of CD64 targeting of antigen to professional antigen presenting cells (APC), overlayed with various strategies of APC activation, to amplify T cell responses in human systems to prostate cancer related antigens. In Project 5 augmentation of antigen loading and activation of dendritic cell (DC) APC form the foundation for both preclinical studies and clinical trials to define DC-based vaccines for colorectal cancer. Together these projects will contribute to defining creative new ways by which immune responses can be modulated either positively to combat tumors and bacterial infections, or in a down-regulatory manner to lessen unwanted inflammation and autoimmunity.