COBRE: DMS: CD1 ACQUISITION OF BCR & FC RECEPTOR TARGETED LIGAND

描述(由申请人提供)：本公司的最终目标 申请将增加新罕布夏州调查人员的数量 是否有竞争力获得NIH的外部资金，并建立一个 免疫和炎症中心将得到国家认可并免费 再过五年。基于现有的高度交互的核心 达特茅斯医学院(DMS)协作和多学科教师 和达特茅斯希区柯克医疗中心(DHMC)，以及几个关键的教职员工 在达勒姆的新汉普郡大学(UNH)，科布雷机制将 提供资源以促进该计划在教师发展方面的发展 以及获得功能中心地位所需的基础设施。教员 Cobre的资金将通过四种方式促进增长：1)招聘 五名终身教职教师：两名在新汉普郡大学，三名 在DMS/DHMC；2)指导发展五名有前途的初级调查人员 已经在达特茅斯，作为五项研究的项目负责人。项目； 3)通过Bruce Reinhold博士进一步加强卫生部/卫生部与卫生署之间的联系 (UNH助理教授)，关键的合作调查员，将提供 DMS和DHMC没有光谱专业知识；还有Vernon博士 北卡罗来纳大学的Reinhold(项目3)和Thomas Pistole(项目2)；以及4)协同 通过五个研究项目和相关的科学合作 核心。在私人侦探威廉·R·格林博士的领导下，目前 DMS/DHMC免疫学项目主任和实质性的 卫生与公众服务部/卫生与公众服务部和卫生与公众服务部都作出了机构承诺，因此有信心 强大的现有调查人员基础可以通过 科布雷机制建立一个中心，由将被 在获得NIH外部资金方面更具竞争力，以及 从而加强国家的研究经费组合。 这五个单独的研究项目展示了多学科的广度。 中心的特征，但也由共同的主题交织在一起 在各种疾病状态下的免疫调节，都处于非特异性水平 炎症过程以及与特定适应性有关的 豁免权。项目1检查细胞因子肿瘤坏死的中心作用 炎症过程和自身免疫性疾病中的α因子(TNF-a)，以及 转录后水平对T淋巴细胞产生肿瘤坏死因子-α的调节 控制信使核糖核酸稳定性。项目2研究了 巨噬细胞活化和细胞因子，特别是转化生长因子-β1，在 内毒素致感染性休克的炎症过程 来自革兰氏阴性菌，以及在转化生长因子-β1中观察到的肝脏炎症- 有缺陷的小鼠。在项目3中，生化和生物物理技术是 用来确定新型亲脂抗原的加工途径。 由CD1表现的结核病，一种单态的1B类表现 分子，作为疫苗开发的基础。项目4利用 CD64靶向专业抗原提呈细胞的方法 (APC)，覆盖各种APC激活策略，以扩增T细胞 人体系统对前列腺癌相关抗原的反应。在项目5中 树突状细胞(DC)APC形式抗原载量的增加和活化 临床前研究和临床试验的基础，以确定基于DC的 结直肠癌疫苗。这些项目加在一起将有助于 定义免疫反应可以被调节的创造性的新方法 要么积极抗击肿瘤和细菌感染，要么下调监管 减少不必要的炎症和自身免疫的方式。

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.