Indoleamine 2,3 Dioxygenase in Colitis Associated Cancer

描述(由申请人提供)： 这份提案描述了一项为期5年的培训计划，旨在发展胃肠病学的学术研究生涯。该协会以前有实验室研究的经验，并接受过胃肠病方面的培训，重点是炎症性肠道疾病。他目前正在扩展他在肠道炎症研究方面的科学技能，特别是当它与炎症相关的癌症发生有关时。威廉·斯坦森博士是一位国际公认的肠道炎症实验室研究专家，他有培训独立科学家的既定记录，并将提供主要指导。为了进一步促进研究人员的科学发展，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长的备受尊敬的内科科学家组成。该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)，及其在慢性肠炎和炎症相关的结直肠癌(CRC)中的作用。炎症性肠病及其并发症在受影响的个人及其家庭中会导致显著的发病率。结肠炎相关性癌症是最令人恐惧的并发症之一。有几条证据表明，国际开发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被认为是通过抑制淋巴细胞激活而起作用的。我们的证据表明，IDO在肠道上皮细胞中高表达，以响应炎症和Toll样受体的激活。IDO在上皮细胞中的这种表达在葡聚糖硫酸钠结肠炎中起到保护作用，葡聚糖硫酸钠结肠炎是一种不依赖T细胞的上皮功能障碍模型。这些研究的目的是为深入了解IDO在慢性结肠炎和结肠炎相关性结肠癌中的T细胞依赖和上皮细胞依赖功能提供关键的见解，阐明针对影响结肠炎和结肠癌IDO活性的治疗药物的潜在作用。包括基因敲除和转基因小鼠在内的科学工具将有助于实现特定目标，包括1)评估IDO在T细胞依赖和非依赖的慢性结肠炎模型中的作用；2)确定IDO在结肠上皮和癌细胞增殖中的作用；3)确定IDO在结肠炎相关癌症模型中的T细胞依赖和非依赖功能。申请者和这项有指导的研究资助的更大目标是发展成为一名独立研究人员所需的知识和技能，并提出相关的粘膜免疫学基本问题，以帮助我们了解人类胃肠道炎症性疾病。

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.