COBRE CORE B: DMS: MOLECULAR BIOLOGY CORE/IMMUNE MONITORING LABORATORY

描述（由申请人提供）：本COBRE的最终目标 申请是为了增加新罕布什尔州的调查人员， 有竞争力的m确保国家卫生研究院的校外资金，并建立一个 免疫学和炎症中心，将得到国家承认和免费 站在五年。基于现有的高度互动的核心 达特茅斯医学院（DMS）的合作和多学科教师 和达特茅斯希区柯克医学中心（DHMC），沿着有几个关键的教师 在位于达勒姆的新罕布什尔州大学，COBRE机制将 提供资源，在教师发展方面发展该计划 以及获得功能中心地位所需的基础设施。教师 COBRE的资金将通过四种方式促进增长：1）招募 五名终身教职教师：两名在新罕布什尔州大学，三名在 2）指导五名有前途的初级调查员的发展 已经在达特茅斯，作为五个研究项目的负责人。项目; 3)DMS/DHMC和UNH之间通过布鲁斯·莱因霍尔德博士进一步建立联系 （UNH助理教授），一个关键的共同研究者谁将提供质量 DMS和DHMC不具备光谱学专业知识;还有弗农博士 联合国海地办事处的Reinhold（项目3）和托马斯皮斯托尔（项目2）; 4）协同增效 通过五个研究项目和相关的科学合作 丹在P.I.的领导下，William R.绿色，电流 DMS/DHMC免疫学项目主任， 由于移民管理局/卫生监测中心和联合国海地办事处都作出了机构承诺， 现有的强大调查人员基础可以通过 COBRE机制建立一个中心，由教师组成，他们将 在获得NIH校外资助方面更具竞争力， 从而加强国家的研究资助组合。 五个独立的研究项目展示了多学科的广度 一个中心的特点，但也交织着共同的主题， 在各种疾病状态下调节免疫力，无论是在非特异性水平， 炎症过程以及特定的适应性 免疫力项目1研究了细胞因子肿瘤坏死的中心作用 因子α（TNF-α）在炎症过程和自身免疫性疾病中的作用， 在转录后水平调节T淋巴细胞中TNF-α的产生 控制mRNA的稳定性。项目2研究的角色， 巨噬细胞活化和细胞因子，特别是TGF-β 1，在 内毒素诱导感染性休克的炎症过程 从革兰氏阴性菌，并在肝脏炎症中观察到TGF-β 1- 缺陷小鼠在项目3中，生物化学和生物物理技术 用于确定新的M亲脂性抗原的加工途径。 以CD 1为表现的结核病，一种单形性1B型结核病， 作为疫苗开发的基础。项目4利用 一种CD 64靶向抗原至专职抗原呈递细胞的方法 (APC)，叠加各种APC激活策略，以扩增T细胞， 在人类系统中对前列腺癌相关抗原的反应。项目5 抗原负载的增加和树突状细胞（DC）APC形式的活化 临床前研究和临床试验的基础，以定义基于DC的 结肠直肠癌的疫苗这些项目将有助于 来定义新的免疫反应调节方式 无论是积极对抗肿瘤和细菌感染，还是在下调 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.