The tumor-suppressive role of ALK4/ACVR1B in pancreatic tumorigenesis

ALK4/ACVR1B 在胰腺肿瘤发生中的抑癌作用

• 批准号: 7640642
• 负责人: Gloria Huei-Ting Su
• 金额: $ 18.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640642
• 关键词: Activins; Adenocarcinoma; Affect; Animal Model; Belief; Biological; Biology; Breeding; Cancer Etiology; Cancer Model; Cancer Patient; Carcinoma; Cessation of life; Complex; Country; Cystic Neoplasm; Data; Designer Drugs; Detection; Development; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Embryo; Funding; Genes; Genetic; Genetic Engineering; Genotype; Grant; Human; Human Biology; Human Development; Intraductal Papillary Breast Carcinoma; Knockout Mice; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Marker Discovery; Mediator of activation protein; Modeling; Mucinous Neoplasm; Mus; Mutation; Oncogenes; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Papillary; Pathway interactions; Patients; Progress Review Group; Publishing; Reporting; Research Priority; Role; Sampling; Signal Pathway; Simulate; Specimen; Tumor Markers; Tumor Suppression; Tumor Suppressor Genes; Type I Activin Receptors; Uncertainty; base; bone morphogenetic protein receptors; cancer prevention; cancer type; effective therapy; gastrulation; in vivo; infiltrating duct carcinoma; insight; mouse model; neoplastic; outcome forecast; pancreatic tumorigenesis; receptor; tool; tumor; tumor progression; tumorigenesis

Pancreatic cancer is the fifth leading cause of cancer death in this country and it is almost uniformly fatal. The poor prognosis of pancreatic cancer patients can be attributed to the lack of early detections and effective treatments. Genetic engineered mice have been effective tools for cancer modeling and pathway studies. A genetic engineered mouse model that simulate a cancer type can be utilized for tumor marker discovery and contribute to the development of early detections. It can also further our understanding of a particular signaling pathway that is important for pancreatic tumorigenesis and lead to the development of designer drugs that are pathway-specific. Here we propose to study activin signaling pathway in genetic engineered mice, because we have previously shown that activin signaling pathway is important for human pancreatic tumorigenesis and this pathway and its funiton in tumor-suppression have not been investigated in vivo. The TGFa receptor superfamily (TGFa, activin, and BMP receptors) and their mediators are critical to pancreatic development and tumorigenesis. We have shown previously that activin type I receptor B (ALK4/ACVR1B) is a tumor-suppressor gene that is biallelically inactivated in pancreatic ductal adenocarcinoma. However, its function in pancreatic tumorigenesis is largely unknown. The objective of this proposal is to investigate the tumor-suppressive function of ALK4/ACVR1B in pancreatic tumorigenesis in Alk4 conditional knock-out mouse models because conventional knockout mice at the Alk4 gene locus are embryonic lethal. We will also investigate the intrinsic relationship between Alk4 and Smad4 in tumor suppression in a compound knock-out mouse model. In addition, we would like to explore the possible role of ALK4/ACVR1B in a subset of pancreatic early lesions called intraductal papillary mucinous neoplasm (IPMN), which is distinct from pancreatic ductal adenocarcinoma and its early lesions (pancreatic intraepithelial neoplasia, PanIN). The involvement of ALK4/ACVR1B has not been evaluated in IPMN previously. It is our belief that to understand the biology of the cancer genes that contribute to the development of human pancreatic cancer will help us develop better detection and treatment options. The urgency to detect and treat this deadly disease has prompted the NCI to issue a Progress Review Group report, in which the NCI identifies the development of ?gene-based model systms that faithfully parallel the complex biology of human pancreatic cancer? as one of its research priorities (http://planning.cancer.gov/pdfprgreports/2001pancreatic.pdf). Gene-based animal models that recapitulate human pancreatic cancer will become avaialbe if this proposal is funded. This grant is 100% relevant to pancreatic cancer.

胰腺癌是美国癌症死亡的第五大原因， 都是致命的胰腺癌患者的预后差可归因于缺乏早期治疗。 检测和有效治疗。基因工程小鼠是治疗癌症的有效工具 建模和路径研究。模拟癌症类型的基因工程小鼠模型可以 用于肿瘤标志物的发现，并有助于早期检测的发展。它也可以 进一步了解一个特殊的信号通路，这是重要的胰腺 肿瘤发生，并导致设计药物的发展，是特定的途径。这里我们 建议在基因工程小鼠中研究激活素信号通路，因为我们以前已经 显示激活素信号通路对于人胰腺肿瘤发生是重要的， 通路及其在肿瘤抑制中的作用尚未在体内研究。 TGF α受体超家族（TGF α、激活素和BMP受体）及其介导物是 对胰腺发育和肿瘤发生至关重要。我们以前已经证明，I型激活素 受体B（ALK 4/ACVR 1 B）是一种在胰腺中双等位基因失活的肿瘤抑制基因 导管腺癌然而，其在胰腺肿瘤发生中的功能在很大程度上是未知的。的 本研究的目的是研究ALK 4/ACVR 1B在肿瘤细胞中的肿瘤抑制功能。 Alk 4条件性基因敲除小鼠模型中的胰腺肿瘤发生， Alk 4基因位点的小鼠是胚胎致死的。我们还将研究 Alk 4和Smad 4在化合物敲除小鼠模型中的肿瘤抑制中的关系。 此外，我们还想探讨ALK 4/ACVR 1B在胰腺癌早期发病中的可能作用。 称为导管内乳头状粘液性肿瘤（IPMN）的病变，与胰腺癌不同， 导管腺癌及其早期病变（胰腺上皮内瘤变，PanIN）。的 ALK 4/ACVR 1B的参与以前没有在IPMN中进行评估。 我们相信，要了解癌症基因的生物学， 人类胰腺癌的发展将有助于我们开发更好的检测和治疗方案。 检测和治疗这种致命疾病的紧迫性促使NCI发布了一份进展报告 小组报告，其中NCI确定的发展？基于基因的模型系统 与人类胰腺癌的复杂生物学完全平行吗作为其研究重点之一 (http：//planning.cancer.gov/pdfprgreports/2001pancreatic.pdf）。基于基因的动物模型 概括地说，如果该提案获得资助，人类胰腺癌将成为可能。这笔赠款是 与胰腺癌100%相关。