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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：
9136655
负责人：
LESZEK KOTULA
金额：
$ 33.39万
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/9136655
关键词：
1-Phosphatidylinositol 3-Kinase 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 Funding Agency Gene Expression Genes Genetically Engineered Mouse Goals Growth Health Health Personnel Histologic Histopathology Human Knock-out Knockout Mice Knowledge LNCaP Laboratories Lead LoxP-flanked allele 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 knock-down male men mouse model new therapeutic target novel novel therapeutics pre-clinical probasin prostate cancer prevention prostate carcinogenesis recombinase senescence statistics success targeted cancer therapy 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(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(今年约为3.2万人)，也是美国男性主要的确诊癌症(2012年约有241,000例新病例)。最近，新诊断的前列腺癌病例数量有所上升。这些令人震惊的统计数据需要临床医生、医疗保健提供者、科学界和资助机构给予特别关注。不同的基因变化已被确定为导致男性前列腺癌。癌症患者肿瘤形成的常见机制之一是一个或多个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。我们的团队已经确定了一个这样的肿瘤抑制基因，Abi1/Hssh3bp1，并开发了一个新的条件基因敲除小鼠模型，以研究该基因在前列腺癌发生中的作用。Abi1/Hssh3bp1基因的前列腺特异性破坏导致前列腺上皮内瘤变(PIN)的发生。鉴于我们公布的数据表明，ABI1KO小鼠观察到的前列腺病理是PI-3激酶-Akt通路异常调节的细胞间黏附和激活的结果，该小鼠模型提供了一个急需的基于机制的动物模型，利用该模型可以详细研究ABI1‘S的肿瘤抑制作用以及它在导致前列腺癌的肿瘤过程启动中的作用。此外，我们从实验室产生的其他小鼠模型中获得的初步数据表明，ABI1作用于前列腺癌最常见的突变基因PTEN的下游，并调节肿瘤的侵袭。更好地了解ABI1的S功能可能会为前列腺癌的治疗提供新的治疗选择，并为前列腺癌的翻译研究建立新的小鼠模型。