Indoleamine 2,3 Dioxygenase in Colitis Associated Cancer

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，以发展胃肠病学的学术研究事业。PI具有实验室研究的既往经验，并接受过胃肠病学研究员培训，重点关注炎症性肠病。他目前正在扩大他在肠道炎症研究方面的科学技能，特别是因为它与炎症相关的致癌作用有关。William Stenson博士是国际公认的肠道炎症实验室研究专家，在培训独立科学家方面拥有良好的记录，并将提供原则指导。为了进一步促进研究者的科学发展，成立了一个咨询委员会，由在肠道炎症以及癌症和上皮细胞生物学方面具有专业知识的德高望重的医生科学家组成。PI机构的研究环境提供了丰富的智力和调查资源网络，以支持职业发展。拟议的研究重点是一种具有公认的免疫调节特性的酶，吲哚胺2，3双加氧酶（IDO），及其在慢性肠道炎症和炎症相关的结肠直肠癌（CRC）中的作用。炎症性肠病及其并发症导致受影响个体及其家庭的显著发病率。结肠炎相关癌症是最可怕的并发症之一。有几方面的证据表明，国际采矿组织在这些进程中发挥了作用;然而，这一领域在很大程度上仍未得到探索。IDO被视为通过抑制淋巴细胞活化而起作用。我们的证据表明，IDO在肠道上皮细胞中高度表达，以响应炎症和toll样受体激活。IDO在上皮细胞中的这种表达在葡聚糖硫酸钠结肠炎中起保护作用，葡聚糖硫酸钠结肠炎是一种不依赖于T细胞的上皮功能障碍模型。这些研究的目标是提供对IDO在慢性结肠炎和结肠炎相关结肠癌中的T细胞依赖性和上皮细胞依赖性功能的关键性见解，阐明针对影响IDO活性的治疗剂在结肠炎和结肠恶性肿瘤中的潜在作用。包括敲除和转基因小鼠系的科学工具将有助于解决具体目标，包括1）评估IDO在慢性结肠炎的T细胞依赖性和非依赖性模型中的作用，2）确定IDO在结肠上皮和癌细胞增殖中的作用，和3）定义IDO在结肠炎相关癌症模型中的T细胞依赖性和非依赖性功能。申请人的更大目标和这个指导研究补助金是发展所需的知识和技能，成为一个独立的研究者，并询问粘膜免疫学的相关基本问题，帮助我们了解人类胃肠道炎性疾病。 公共卫生相关性： 这些研究的目的是提供对IDO在慢性结肠炎和结肠炎相关结肠癌中的淋巴细胞依赖性和上皮细胞依赖性功能的关键见解，如在人克罗恩病和溃疡性结肠炎中发生的那样。这项工作的相关性是澄清针对影响IDO活性的治疗剂在结肠炎和结肠恶性肿瘤中的潜在作用。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic research career in gastroenterology. The PI has previous experience in laboratory investigation and is fellowship trained in gastroenterology with a focus in the inflammatory bowel diseases. He is currently expanding his scientific skills in investigation of intestinal inflammation, particularly as it relates to inflammation associated carcinogenesis. Dr William Stenson, an internationally recognized expert in laboratory investigations in intestinal inflammation has an established record of training independent scientists and will provide principle mentorship. To further promote the investigator's scientific development an advisory committee comprising of highly regarded physician scientist with expertise in intestinal inflammation as well as cancer and epithelial cell biology has been established. The research environment at the PI's institution provides a rich network of intellectual and investigational resources to support career development. The proposed research focuses on an enzyme with recognized immunomodulatory properties, Indoleamine 2,3 Dioxygenase (IDO), and its role in chronic intestinal inflammation and inflammation-associated colon-rectal cancer (CRC). The inflammatory bowel diseases and their complications lead to significant morbidity in affected individuals and their families. Colitis associated cancer is one of the most feared complications. Several lines of evidence suggest a role for IDO in these processes; however the area remains largely unexplored. IDO is seen as acting through the inhibition of lymphocyte activation. Our evidence shows that IDO is highly expressed in gut epithelial cells in response to inflammation and toll-like receptor activation. This expression of IDO in epithelial cells serves a protective function in dextran sodium sulfate colitis, a model of epithelial dysfunction which is T-cell independent. The goal of these studies is provide critical insight into the T-cell dependent and epithelial cell dependent functions of IDO in chronic colitis and colitis associated colon cancer, clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon. Scientific tools including knockout and transgenic mouse lines will assist in addressing the specific aims including 1) Evaluating the role of IDO in both T-cell dependent and independent models of chronic colitis 2) Determining the role of IDO in colon epithelial and cancer cell proliferation, and 3) Defining T-cell dependent & independent functions of IDO in a model of colitis associated cancer. The larger goal of the applicant and this mentored research grant is to develop the knowledge and skill sets required to become an independent investigator and ask relevant basic questions in mucosal immunology that aid in our understanding of human inflammatory diseases of the gastrointestinal tract. PUBLIC HEALTH RELEVANCE: The goal of these studies is provide critical insight into the lymphocyte dependent and epithelial cell dependent functions of IDO in chronic colitis as and colitis associated colon cancer as occurs in human Crohn's and Ulcerative Colitis. The relevance of this work is to clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon.