Indoleamine 2,3 Dioxygenase in Colitis Associated Cancer

结肠炎相关癌症中的吲哚胺 2,3 双加氧酶

• 批准号: 8500253
• 负责人: MATTHEW AARON CIORBA
• 金额: $ 14.21万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500253
• 关键词: Acute; Address; Adenocarcinoma; Advisory Committees; Affect; Apoptosis; Area; Azoxymethane; Biology; Blood Vessels; Cancer Model; Cell Line; Cell Proliferation; Cells; Cellular biology; Chronic; Colitis; Colon; Colon Carcinoma; Data; Development; Dioxygenases; Disease; Dysplasia; Environment; Enzymes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Family; Fellowship; Fright; Functional disorder; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Genes; Goals; Growth; HCT116 Cells; Human; Immune; Immune system; Immunocompetent; Immunodeficient Mouse; Immunologic Surveillance; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Institution; Interferons; Intestines; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Mediating; Mentors; Mentorship; Metastatic Neoplasm to the Liver; Modeling; Morbidity - disease rate; Morphology; Mus; Neoplasm Metastasis; Nude Mice; Oncogene Activation; Pathway interactions; Physicians; Population; Process; Program Development; Property; Proto-Oncogenes; Receptor Activation; Rectal Cancer; Relative (related person); Research; Research Personnel; Research Project Grants; Resources; Role; Scientist; Severities; Severity of illness; Site; Sodium Dextran Sulfate; T cell response; T-Lymphocyte; Testing; Therapeutic Agents; Toll-like receptors; Training; Training Programs; Transfection; Transgenic Mice; Transgenic Organisms; Ulcerative Colitis; Up-Regulation; Work; Xenograft procedure; antimicrobial; base; cancer cell; carcinogenesis; career; career development; colitis associated cancer; colonic crypt; experience; improved; in vivo; indoleamine; insight; large bowel Crohn' s disease; laser capture microdissection; migration; model development; mouse model; neoplastic cell; novel; overexpression; public health relevance; repaired; response; skills; tool; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）： 该提案描述了一个为期 5 年的胃肠病学学术研究职业发展培训计划。 PI 之前有实验室调查经验，并接受过胃肠病学专科培训，重点研究炎症性肠病。他目前正在扩大他在肠道炎症研究方面的科学技能，特别是与炎症相关的致癌作用。 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备受尊敬的医师科学家组成的咨询委员会。 PI 机构的研究环境提供了丰富的知识和研究资源网络来支持职业发展。拟议的研究重点关注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的个人及其家庭显着发病。结肠炎相关癌症是最可怕的并发症之一。多项证据表明 IDO 在这些过程中发挥着重要作用；然而，该地区基本上仍未被勘探。 IDO 被视为通过抑制淋巴细胞活化发挥作用。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 样受体激活。 IDO 在上皮细胞中的表达在葡聚糖硫酸钠结肠炎中发挥保护作用，这是一种不依赖于 T 细胞的上皮功能障碍模型。这些研究的目的是深入了解 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，阐明直接影响 IDO 活性的治疗药物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在内的科学工具将有助于实现以下具体目标：1) 评估 IDO 在 T 细胞依赖性和独立性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，以及 3) 定义 IDO 在结肠炎相关癌症模型中的 T 细胞依赖性和独立功能。申请人和这项指导性研究资助的更大目标是发展成为独立研究者所需的知识和技能，并提出粘膜免疫学方面的相关基本问题，以帮助我们了解人类胃肠道炎症性疾病。 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（如在人类克罗恩病和溃疡性结肠炎中发生）中的淋巴细胞依赖性和上皮细胞依赖性功能的重要见解。这项工作的意义在于阐明治疗药物在结肠炎和结肠恶性肿瘤中影响 IDO 活性的潜在作用。