Mechanism of PIN development in Abi1/Hssh3bp1 KO mouse

Abi1/Hssh3bp1 KO 小鼠 PIN 发育机制

基本信息

批准号：
8581821
负责人：
LESZEK KOTULA
金额：
$ 34.87万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581821
关键词：
1-Phosphatidylinositol 3-Kinase ABI1 gene American Animal Model Attention Breeding Cancer Diagnostics Cancer Etiology Cancer Patient Carcinoma Cell Adhesion Cell Line Cells Cessation of life Characteristics Communities Complex Data Development Diagnosis Diagnostic Procedure Dose Drug Targeting Funding Agency Gene Expression Genes Genetically Engineered Mouse Goals Growth Health Personnel Histologic Histopathology Human Knock-out Knockout Mice Knowledge LNCaP Laboratories Lead Malignant Neoplasms Malignant neoplasm of prostate Maps Modeling Molecular Target Mouse Strains Mus Mutate Mutation Neoplastic Processes Normal tissue morphology PTEN gene Pathology Pathway interactions Physiological Pre-Clinical Model Process Prostate Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Publishing Research Research Proposals Role Signal Pathway Signal Transduction Site Small Interfering RNA Tissues Translational Research Tumor Cell Invasion Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Tumor-Suppressor Gene Inactivation Tumorigenicity United States Work base beta catenin cancer diagnosis cancer initiation cancer therapy cell growth cell growth regulation drug testing male men mouse model novel novel therapeutics pre-clinical probasin prostate cancer prevention prostate carcinogenesis public health relevance recombinase senescence statistics success tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the leading cause of male cancer-related deaths in the United States (about 32,000 this year) and the leading diagnosed cancer in American men (about 241,000 new cases in 2012). The number of new prostate cancer diagnoses has risen recently. These alarming statistics require special attention from clinicians, healthcare providers, scientific communities, and funding agencies. Different genetic changes have been identified to cause prostate cancer in men. One of the common mechanisms of tumor formation in cancer patients is inactivation of one or more so- called tumor suppressor genes. Inactivation of tumor suppressor genes has devastating consequences on the regulation of cell growth within a specific tissue and results in tumor development. Our group has identified one such tumor suppressor gene, Abi1/Hssh3bp1, and has developed a novel conditional knockout mouse model to study the role of this gene in development of prostate cancer. Prostate-specific disruption of the Abi1/Hssh3bp1 gene leads to development of prostatic intraepithelial neoplasia (PIN). Given our published data indicating that the observed prostate pathology in Abi1 KO mice is the result of abnormally regulated cell- to-cell adhesion and activation of PI-3 kinase-Akt pathway, this mouse model provides a much- needed mechanistically based animal model with which to conduct detailed studies of Abi1's tumor suppressive role as well as its role in the initiation of neoplastic processes leading to prostate cancer. Moreover, our preliminary data from additional mouse models generated in the lab indicate that Abi1 acts downstream from the most commonly mutated gene in prostate cancer, PTEN, and regulates tumor invasion. A better understanding of Abi1's function might lead to new therapeutic options for the treatment of prostate cancer and establishment of the novel mouse model for translational research in prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的主要原因（今年约有 32,000 例），也是美国男性诊断出的主要癌症（2012 年约有 241,000 例新病例）。最近新诊断的前列腺癌数量有所增加。这些令人震惊的统计数据需要临床医生、医疗保健提供者、科学界和资助机构的特别关注。已发现不同的基因变化会导致男性前列腺癌。癌症患者中肿瘤形成的常见机制之一是一种或多种所谓的肿瘤抑制基因的失活。肿瘤抑制基因的失活对特定组织内细胞生长的调节具有毁灭性的后果，并导致肿瘤的发展。我们的研究小组已经鉴定了一个这样的肿瘤抑制基因，Abi1/Hssh3bp1，并开发了一种新型条件敲除小鼠模型来研究该基因在前列腺癌发展中的作用。 Abi1/Hssh3bp1 基因的前列腺特异性破坏会导致前列腺上皮内瘤变 (PIN) 的发展。鉴于我们发表的数据表明，在 Abi1 KO 小鼠中观察到的前列腺病理学是异常调节的细胞间粘附和 PI-3 激酶-Akt 通路激活的结果，该小鼠模型提供了一种急需的基于机制的动物模型对 Abi1 的肿瘤抑制作用及其在导致前列腺癌的肿瘤过程启动中的作用进行详细研究。此外，我们从实验室生成的其他小鼠模型中获得的初步数据表明，Abi1 在前列腺癌中最常见的突变基因 PTEN 的下游发挥作用，并调节肿瘤侵袭。更好地了解 Abi1 的功能可能会为治疗前列腺癌带来新的治疗选择，并建立用于前列腺癌转化研究的新型小鼠模型。