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

胰腺癌是这个国家第五大癌症死亡原因，它几乎是 都是致命的。胰腺癌患者预后不良可归因于缺乏早期治疗。 检测和有效的治疗。基因工程小鼠已成为治疗癌症的有效工具 建模和路径研究。一种模拟癌症类型的基因工程小鼠模型可以 用于发现肿瘤标记物，并有助于早期检测的发展。它还可以 进一步了解对胰腺非常重要的特定信号通路 肿瘤的发生和导致针对特定途径的设计药物的开发。在这里我们 建议研究基因工程小鼠的激活素信号通路，因为我们之前已经 激活素信号通路在人胰腺肿瘤发生中起重要作用 其途径及其在肿瘤抑制中的作用尚未在体内进行研究。 TGFa受体超家族(TGFa、激活素和BMP受体)及其介体是 对胰腺发育和肿瘤发生至关重要。我们之前已经证明了激活素I型 B受体(ALK4/ACVR1B)是一种在胰腺中双等位失活的肿瘤抑制基因 导管腺癌。然而，它在胰腺肿瘤发生中的作用在很大程度上还不清楚。这个 本研究的目的是探讨ALK4/ACVR1B对小鼠肿瘤的抑制作用。 Alk4条件性基因敲除小鼠模型胰腺肿瘤的发生 Alk4基因座上的小鼠对胚胎是致命的。我们还将研究内在的 Alk4和Smad4在复合基因敲除小鼠肿瘤抑制中的关系。 此外，我们还想探讨ALK4/ACVR1B在早期胰腺癌中的可能作用。 称为导管内乳头状粘液性肿瘤(IPMN)的病变，与胰腺不同 导管腺癌及其早期病变(胰腺上皮内瘤变，Panin)。这个 ALK4/ACVR1B的参与以前没有在IPMN中被评估过。 我们认为，要了解癌症基因的生物学特性， 人类胰腺癌的发展将帮助我们开发更好的检测和治疗方案。 发现和治疗这种致命疾病的紧迫性促使NCI发布了一份进度回顾 小组报告，其中NCI确定了基于基因的模型系统的发展 忠实地与人类胰腺癌的复杂生物学相比较？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 如果这项提案得到资助，概括性的人类胰腺癌将成为可能。这笔赠款是 100%与胰腺癌相关。

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.