Role of the BMP SMADs in Oncogenesis

BMP SMAD 在肿瘤发生中的作用

基本信息

批准号：
8205009
负责人：
STEPHANIE A. PANGAS
金额：
$ 35.44万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8205009
关键词：
Activins Address Adolescent Adult Alleles BMP7 gene Bone Morphogenetic Proteins Cell Differentiation process Cell Proliferation Cells Colorectal Neoplasms Data Development Developmental Process Diagnostic Disease Embryo Family Female Future Generations Gene Expression Gene Expression Profile Genes Genetic Genetic Models Goals Gonadal structure Growth Factor Human In Vitro Knock-out Knockout Mice Knowledge Lead Ligands Link Lymphatic Metastasis MADH2 gene MADH3 gene MADH4 gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenes Ovarian Follicle Ovary Pancreatic carcinoma Pathogenesis Pathologic Pathway interactions Peritoneal Phenotype Physiological Physiological Processes Platelet-Derived Growth Factor Play Property Protein Family Protein Isoforms Proteins Role Sex Cord-Gonadal Stromal Tumors Signal Pathway Signal Transduction Signal Transduction Pathway Somatic Cell Somatic Mutation Subgroup Testing Testis Tissues Transcriptional Regulation Transforming Growth Factor beta Transforming Growth Factors Tumor Angiogenesis Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation Work aged angiogenesis arm base bone cell growth cell type gonadal cancer granulosa cell granulosa cell tumor human disease in vivo leydig interstitial cell male mouse model mutant neoplastic cell neovascularization novel novel diagnostics null mutation promoter protein function public health relevance recombinase reproductive sertoli cell tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The proteins that comprise the transforming growth factor beta (TGF?) family have wide-ranging developmental and physiologic functions. Dysregulation of various TGF? family signaling has been linked to cancer and other diseases including those of the reproductive tract. The TGF? family can be divided into two main subgroups: the TGF?/activins and the bone morphogenetic proteins (BMPs). Both subgroups use the SMAD pathway as the canonical signaling pathway, but utilize different isoforms: SMAD2 and SMAD3 (called the AR-SMADs) signal for TGF? and activin, while SMAD1, SMAD5, and SMAD8 (called the BR-SMADs) signal for the BMPs. We have developed a mouse model for deletion of Smad1 and Smad5 in the somatic cells of the gonad and these mice develop metastatic gonadal cancers. While our preliminary data clearly indicate a role for the BR-SMADs in tumor suppression, the mechanism behind tumorigenesis and metastasis development is unknown. The overall goal of this proposal is to dissect the mechanism behind tumor suppression by the BR-SMADs using existing and newly-created mouse models, and to examine these same mechanisms during the pathogenesis of human granulosa cell tumors. Both in vivo and in vitro studies will be used to analyze the function of the BR-SMADs in regulating tumor formation in the gonad and other tissues, particularly with respect to control of gene expression. Specific Aims 1 and 2 utilize study the interrelationship between the TGF? and BMP SMAD pathways as they relate to gonadal tumorigenesis in mice and humans. The third aim investigates the role of the BR-SMADs as regulators of tumor angiogenesis. These studies will define essential roles for the BMP and TGF? ligands as they relate to oncogenesis in the ovary and generate key genetic models for understanding the development of cancer. PUBLIC HEALTH RELEVANCE: Developmental signaling pathways are often misregulated in cancer. New mouse models have uncovered a novel role for the bone morphogenetic pathway in regulating gonadal cancer, although the mechanism behind tumor and metastasis formation in this model is unclear. Understanding how the SMAD pathway controls cell growth and differentiation in normal and pathologic tissues will allow us understand genetic disruptions in this signaling pathway in human cancers, as well as to tailor diagnostics and treatment regimes based on a molecular understanding of the TGF? family pathway.

描述（由申请人提供）：构成转化生长因子β（TGF？）家族的蛋白质具有广泛的发育和生理功能。各种TGF的失调？家庭信号传导与癌症和其他疾病（包括生殖道疾病）有关。转化生长因子？该家族可分为两个主要亚组：TGFβ/激活素和骨形态发生蛋白(BMP)。两个亚组均使用 SMAD 途径作为经典信号传导途径，但利用不同的同工型：SMAD2 和 SMAD3（称为 AR-SMAD）为 TGF? 提供信号？和激活素，而 SMAD1、SMAD5 和 SMAD8（称为 BR-SMAD）为 BMP 发出信号。我们开发了一种小鼠模型，用于删除性腺体细胞中的 Smad1 和 Smad5，这些小鼠会患上转移性性腺癌。虽然我们的初步数据清楚地表明 BR-SMAD 在肿瘤抑制中的作用，但肿瘤发生和转移发展背后的机制尚不清楚。该提案的总体目标是使用现有和新创建的小鼠模型剖析 BR-SMAD 抑制肿瘤背后的机制，并在人类颗粒细胞肿瘤的发病机制中检查这些相同的机制。体内和体外研究将用于分析 BR-SMAD 在调节性腺和其他组织肿瘤形成中的功能，特别是在基因表达的控制方面。具体目标 1 和 2 利用研究 TGF? 之间的相互关系？和 BMP SMAD 途径，因为它们与小鼠和人类的性腺肿瘤发生有关。第三个目标是研究 BR-SMAD 作为肿瘤血管生成调节剂的作用。这些研究将确定 BMP 和 TGF 的重要作用？配体，因为它们与卵巢肿瘤发生有关，并产生了解癌症发展的关键遗传模型。公共健康相关性：癌症中的发育信号通路经常受到错误调节。新的小鼠模型揭示了骨形态发生途径在调节性腺癌中的新作用，尽管该模型中肿瘤和转移形成背后的机制尚不清楚。了解 SMAD 通路如何控制正常和病理组织中的细胞生长和分化，将使我们能够了解人类癌症中该信号通路的遗传破坏，并根据对 TGF? 的分子理解来定制诊断和治疗方案？家庭途径。