The role of MTGR1 in intestinal biology and inflammation

MTGR1 在肠道生物学和炎症中的作用

• 批准号: 7362123
• 负责人: Christopher S. Williams
• 金额: $ 14.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7362123
• 关键词: Acceleration; Acute; Acute Myelocytic Leukemia; Advisory Committees; Affect; Animal Model; Animals; Apoptosis; Apoptotic; Binding; Biology; Carcinoma; Cell Cycle; Cell Line; Cell Survival; Chromosomal translocation; Chronic; Colitis; Colon; Defect; Developed Countries; Developing Countries; Development; Disease; Disease susceptibility; Distal; Enterocytes; Epigenetic Process; Epithelial; Epithelial Cells; Exhibits; Family member; Fellowship; Gene Expression; Gene Family; Gene Proteins; Genes; Genetic Engineering; Genus Cola; Hematopoietic Neoplasms; High Prevalence; Immigration; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Injury; Intestines; Laboratories; Maps; Medicine; Mentors; Midgut; Modeling; Molecular; Mus; Myelogenous; Other Genetics; Pathology; Pathway interactions; Pattern; Pediatrics; Perinatal; Phenotype; Physicians; Play; Postdoctoral Fellow; Predisposition; Prevention; Process; Program Development; Protein Binding; Protein Family; Reagent; Regulation; Regulator Genes; Research; Research Personnel; Residencies; Role; Scientist; Secondary to; Signal Transduction; Small Intestines; Sodium Dextran Sulfate; Stress; Structure; Students; Susceptibility Gene; TCF7L2 gene; Techniques; Testing; Training; Training Programs; Transcription Repressor/Corepressor; Universities; Villus; WNT Signaling Pathway; Week; Work; Wound Healing; base; carcinogenesis; career; cell motility; cell type; gene repression; jejunum; laser capture microdissection; member; migration; professor; programs; pup; repaired; response; response to injury; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an independent translational academic research program. The candidate has completed a structured residency training in Medicine and is completing Gl Fellowship training this year at Vanderbilt University. The proposed program will promote the command of transcriptional corepressor biology, as applied to intestinal inflammatory disease and its sequella. Dr. Scott Hiebert will be the primary mentor for the candidate's scientific development. He is a recognized leader in the field of transcriptional repression and has trained numerous postdoctoral fellows and graduate students. To enhance training, the program will enlist the expertise of Dr. Keith Wilson (Professor of Medicine) and Dr. Brent Polk (Professor of Pediatrics) who have considerable expertise in the field of mucosal immunology and inflammatory bowel disease. In addition, an advisory committee of highly regarded physician scientists will provide scientific and career advice. MTGR1 (Myeloid Translocation Gene, Related-1) is a member of a gene family originally identified as targets of chromosomal translocation in acute myeloid leukemia (AML). Recent work from our laboratory has shown that MTGR1 plays a role in intestinal differentiation, wound healing, and inflammation. We have found that MTG proteins bind TCF4 and repress WNT signal transduction resulting in de-regulation of TCF4 targets. Mtgr1-null animals develop a severe and persistent colitis in response to gut injury and exhibit abnormal enterocyte migration along the crypt-villus access, implicating MTGR1 as a regulator of crypt-villus architectural patterning. Given the role of MTG family members in hematopoietic malignancy, the ability of MTGR1 to modulate WNT signaling, and that loss of MTGR1 results in sensitization to gut injury, we hypothesize that MTGR1 plays a role in inflammatory bowel disease and may contribute to tumorigenesis arising in an inflammatory background. The specific aims include 1) Defining the role of MTGR1 in proliferation, apoptosis, and migration using cell lines derived from wild-type and Mtgr1-/- mice 2) Dissect the contribution of MTGR1 to carcinogenesis using animal models of inflammatory and non-inflammatory carcinogenesis. Inflammatory Bowel Disease (IBD) is predominantly a disease of the 20th century with highest prevalence in developed countries. Abnormalities in MTG family member function may contribute to IBD susceptibility or pathology and potentially to colitis associated carcinoma and thus may offer therapeutic targets for treatment and or prevention of IBD or IBD associated diseases.

描述（由申请人提供）： 该建议描述了一个为期5年的独立翻译学术研究计划的培训计划。候选人已经完成了一项结构化医学培训，并正在范德比尔特大学（Vanderbilt University）完成GL奖学金培训。拟议的程序将促进转录核心生物学的指挥，以适用于肠道炎症性疾病及其后遗症。斯科特·希伯特（Scott Hiebert）博士将成为候选人科学发展的主要导师。他是转录镇压领域的公认领导者，并培训了许多博士后研究员和研究生。为了增强培训，该计划将获得基思·威尔逊（Keith Wilson）博士（医学教授）和布伦特·波尔克（Brent Polk）博士（儿科教授）的专业知识，他们在粘膜免疫学和炎症性肠病领域具有丰富的专业知识。此外，由备受推崇的医师科学家组成的咨询委员会将提供科学和职业建议。 MTGR1（髓样转运基因，相关1）是最初被鉴定为急性髓样白血病（AML）染色体易位靶标的基因家族的成员。我们实验室的最新工作表明，MTGR1在肠道分化，伤口愈合和炎症中起作用。我们发现，MTG蛋白结合TCF4并抑制Wnt信号转导，导致TCF4靶标的下调。 MTGR1无效的动物会因肠道损伤而产生严重而持续的结肠炎，并沿着隐层villus通道表现出异常的肠肠细胞迁移，这意味着MTGR1是密码 - villus建筑构图的调节剂。鉴于MTG家族成员在造血恶性肿瘤中的作用，MTGR1调节Wnt信号的能力以及MTGR1的丧失导致对肠道损伤的敏感性，我们假设MTGR1在炎症性肠病中起着作用，并且可能在炎症背景下引起肿瘤。具体目的包括1）使用源自野生型和MTGR1和MICE的细胞系来定义MTGR1在增殖，凋亡和迁移中的作用2）解剖MTGR1使用炎症性和非炎症性癌变动物模型使用MTGR1对癌变的贡献。炎症性肠病（IBD）主要是20世纪的疾病，发达国家患病率最高。 MTG家庭成员功能异常可能有助于IBD易感性或病理学，并有可能导致与结肠炎相关的癌，因此可能提供治疗靶标，以治疗和预防IBD或IBD相关疾病。