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: 7625939
• 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/7625939
• 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; 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; Susceptibility Gene; TCF7L2 gene; Techniques; Testing; Training; Training Programs; Transcription Repressor/Corepressor; Universities; Villus; WNT Signaling Pathway; Work; Wound Healing; base; carcinogenesis; career; cell motility; cell type; gene repression; graduate student; 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）： 该提案描述了一个为期 5 年的培训计划，用于开发独立的转化学术研究计划。该候选人已经完成了结构化的医学住院医师培训，并将于今年在范德比尔特大学完成 GL 奖学金培训。拟议的计划将促进转录辅阻遏物生物学的控制，应用于肠道炎症性疾病及其后遗症。 Scott Hiebert 博士将成为候选人科学发展的主要导师。他是转录抑制领域公认的领导者，培养了众多博士后和研究生。为了加强培训，该计划将聘请 Keith Wilson 博士（医学教授）和 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拥有丰富的专业知识。此外，由备受尊敬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（骨髓易位基因，Related-1）是最初被确定为急性髓系白血病 (AML) 染色体易位靶标的基因家族的成员。我们实验室最近的工作表明 MTGR1 在肠道分化、伤口愈合和炎症中发挥作用。我们发现 MTG 蛋白结合 TCF4 并抑制 WNT 信号转导，导致 TCF4 靶点失调。 Mtgr1缺失的动物会因肠道损伤而出现严重且持续的结肠炎，并表现出沿着隐窝绒毛通道的异常肠上皮细胞迁移，这表明MTGR1是隐窝绒毛结构模式的调节剂。考虑到 MTG 家族成员在造血系统恶性肿瘤中的作用、MTGR1 调节 WNT 信号传导的能力以及 MTGR1 的缺失导致对肠道损伤的敏感性，我们假设 MTGR1 在炎症性肠病中发挥作用，并可能导致炎症背景下发生的肿瘤发生。具体目标包括 1) 使用源自野生型和 Mtgr1-/- 小鼠的细胞系确定 MTGR1 在增殖、凋亡和迁移中的作用 2) 使用炎症和非炎症癌变动物模型剖析 MTGR1 对癌变的贡献。炎症性肠病（IBD）是 20 世纪的一种主要疾病，在发达国家发病率最高。 MTG家族成员功能异常可能导致IBD易感性或病理学，并可能导致结肠炎相关癌，因此可能为治疗和/或预防IBD或IBD相关疾病提供治疗靶点。