TGF-Beta and Inflammation in Gastric Cancer

TGF-β 与胃癌炎症

基本信息

批准号：
7786283
负责人：
DANIEL B RIFKIN
金额：
$ 18.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786283
关键词：
Age Antibodies Apoptosis Appearance Applications Grants Autoimmune Diseases Binding Binding Proteins Biochemical Biochemistry Biological Models Biology Breeding Cancer Etiology Carcinoma Cell Cycle Cell Proliferation Cells Cellular biology Cessation of life Characteristics Cleaved cell Collagen Complex Cysteine Development Diagnosis Disease Ensure Epithelial Epithelial Cells Epithelium Fibrosis Gastric Adenocarcinoma Generations Genes Genetic Genotype Helicobacter Helicobacter Infections Human Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Laboratories Malignant Neoplasms Marrow Minor Modeling Monitor Mus Mutant Strains Mice Nature Neoplasms Organ Phenotype Prevention Process Production Proteins Reporter Risk Factors Role S-Phase Fraction Serine Signal Transduction Source Stomach Stomach Neoplasms System Testing Therapeutic Intervention Time Tissues Transforming Growth Factor beta Transforming Growth Factors Vascular Diseases base cell growth cytokine design dimer disulfide bond insight interest malignant stomach neoplasm mouse model mutant neoplastic cell novel public health relevance receptor reconstitution rectum/anus research study response single molecule tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): TGF-?, a major regulator of cell growth and inflammation, is secreted primarily as a large latent complex (LLC) consisting of the TGF-? homodimer, the TGF-? propeptide dimer, and a single molecule of the latent TGF-? binding protein (LTBP), which is disulfide bonded to each of the propeptide chains. Association of the propeptide with TGF-? even though the bond between propeptide and TGF-? has been cleaved, renders the TGF-? latent. TGF-? must be freed from the LLC to bind to its receptors. A minor fraction of the latent TGF-? is secreted complexed to its propeptide in the absence of LTBP and is called the small latent complex (SLC). To examine the effect of decreased production of active TGF-? on inflammation and tumor production, we generated mutant mice (Tgfb1C33S/C33S and Tgfb1-/C33S) in which the cysteines in the TGF-?1 propeptide that bind to LTBP were replaced by serines. This mutant TGF-?1 propeptide cannot bind to LTBP. Thus, none of the secreted latent TGF-?1 is bound to an LTBP, but both LTBP and SLC are secreted normally. Tgfb1C33S/C33S mice have multi-organ inflammation, develop tumors of the stomach, rectum and anus, and die by 3-4 months. This phenotype resembles that of the Tgfb1-/- mouse except that the Tgfb1C33S/C33S inflammatory phenotype is milder but the tumor phenotype stronger than the Tgfb1-/- phenotypes. 100% of Tgfb1-/C33S mice develop gastric adenocarcinomas by 12 weeks of age and have a stronger inflammatory response compared to Tgfb1C33S/C33S mice. Our mice are also infected with Helicobacter, a major risk factor for the development of gastric cancer in humans. Thus, Tgfb1-/C33S mice provide a new model system to study gastric adenocarcinoma induction as well as the participation of the inflammatory response in tumorigenesis. Using Tgfb1-/C33S mice as described in this application, we will establish the contribution of inflammation to tumor production - specifically gastric adenocarcinomas, the changes in cell proliferation and apoptosis in the GI epithelium, the role of the inflammatory response in tumor induction, the potential requirement for Helicobacter infection for tumor production, and the source of the tumor cells. We will use a combination of mouse genetics, cell biology, and biochemistry to answer these questions. The successful completion of the proposed experiments will provide information critical to the understanding of the generation of gastric tumors. Such information may yield insights for therapeutic intervention or prevention of gastric tumors. PUBLIC HEALTH RELEVANCE: Gastric tumors are the second leading cause of cancer death worldwide and understanding how the activation of latent TGF-? contributes to the generation of this tumor may have impact for diagnosis and treatment. The mutant mice we have produced provide a novel system for the study of the rapid formation of gastric adenocarcinomas. In addition, these mice may be useful for the study of inflammatory bowel disease as well as other aspects of TGF-? biology.

描述（由申请人提供）：TGF-？是细胞生长和炎症的主要调节剂，主要是由TGF-组成的大型潜在复合物（LLC）分泌。同二聚体，TGF-？前肽二聚体和潜在TGF-的单个分子？结合蛋白（LTBP），该蛋白二硫键粘合到每个丙肽链上。丙肽与TGF-的关联？即使丙肽和TGF-之间的纽带？已经裂了，使TGF-？潜。 tgf-？必须从LLC中释放才能与其受体结合。潜在TGF-的一小部分？在不存在LTBP的情况下被分泌到其丙肽中，称为小型潜伏复合物（SLC）。检查活性TGF-生产降低的影响？在炎症和肿瘤的产生中，我们产生了突变小鼠（TGFB1C33S/C33S和TGFB1-/C33S），其中TGF-？1与LTBP结合的TGF-？1的半胱氨酸被丝氨酸代替。这种突变的TGF-？1丙肽不能与LTBP结合。因此，没有分泌的潜在TGF-？1与LTBP结合，但LTBP和SLC均被分泌正常。 TGFB1C33S/C33S小鼠患有多器官炎症，发展为胃，直肠和肛门的肿瘤，并死亡3-4个月。这种表型类似于TGFB1 - / - 小鼠的表型，除了TGFB1C33S/C33S炎症表型较轻，但肿瘤表型比TGFB1 - / - 表型强。与TGFB1C33S/C33S小鼠相比，TGFB1-/C33S小鼠的TGFB1-/C33S小鼠在12周龄时会发展出胃腺癌。我们的小鼠还感染了Helicobacter，这是人类胃癌发展的主要危险因素。因此，TGFB1-/C33S小鼠为研究胃腺癌诱导以及炎症反应参与肿瘤发生的新模型系统提供了新的模型系统。使用本应用中所述，使用TGFB1-/C33S小鼠，我们将建立炎症对肿瘤产生的贡献，特别是胃腺癌，胃肠道上皮中细胞增殖和凋亡的变化，炎症反应的作用，肿瘤诱导中的作用，在肿瘤诱导中的需求，潜在的细胞产生的螺旋杆菌感染，并为螺旋型的造成和螺旋型的构成而造成螺旋形成。我们将使用小鼠遗传学，细胞生物学和生物化学的组合来回答这些问题。提出的实验的成功完成将为了解胃肿瘤的产生至关重要。这些信息可能会产生治疗干预或预防胃肿瘤的见解。公共卫生相关性：胃肿瘤是全球癌症死亡的第二大原因，并了解潜在TGF-的激活是如何的？有助于该肿瘤的产生可能会影响诊断和治疗。我们生产的突变小鼠为研究胃腺癌的快速形成提供了一种新型系统。此外，这些小鼠可能对研究炎症性肠病以及TGF-的其他方面可能有用？生物学。