Sphinx: a new cause of hepatic neoplasia

Sphinx：肝肿瘤的新病因

• 批准号: 7449784
• 负责人: KASPER HOEBE
• 金额: $ 19.58万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449784
• 关键词: Accounting; Address; Age; Atypical lymphocyte; Biological Models; Birth; Bone Marrow; Bone Marrow Cells; CD8B1 gene; Cancer Etiology; Candidate Disease Gene; Carcinoma; Cessation of life; Chimera organism; Chromosomes, Human, Pair 6; Cirrhosis; Code; Complex; Computer Systems Development; Defect; Development; Embryo; Embryonic Development; Ethylnitrosourea; Etiology; Exhibits; Exons; Functional disorder; Genes; Genetic; Goals; Hematopoietic; Hematopoietic System; Hepatic; Hyperplasia; Immune System Diseases; Immune system; Immunologics; Injury; Laboratories; Link; Liver; Liver Cell Adenoma; Liver neoplasms; Longevity; Lymphocyte; Lymphocyte Subset; Malignant neoplasm of liver; Maps; Mus; Mutant Strains Mice; Mutation; Natural Killer Cells; Neoplasm Metastasis; Neoplasms; Nodule; Organ; Peripheral; Personal Satisfaction; Phenotype; Primary carcinoma of the liver cells; Principal Investigator; Public Health; Splenocyte; Staging; Tissues; Transplantation; Tumor Suppressor Genes; Week; base; mouse model; mutant; neoplastic; neoplastic cell; novel; programs; recessive genetic trait; research study; tumor

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) accounts for 85% of primary malignant tumors of the liver and is the third most-common cause of cancer-related death in the world. Although its etiology is diverse, the development of HCC follows a common pathogenic profile with repetitive hepatic injury leading to cirrhosis, formation of hyperplastic nodules and accumulation of genetic aberrations. Using a forward genetic approach, we have identified an N-ethyl-N-nitrosourea (ENU)-induced germline mutant phenotype, called Sphinx that develops spontaneous multicentric liver tumors. Tumor formation is apparent by 5 weeks of age and histological analyses revealed that the tissue is well differentiated and no etastases were observed. In addition to hepatocellular tumor development, homozygous Sphinx mice exhibit abnormal lymphocyte development and lack peripheral CD8+ T and NK cells. The phenotypes behave as recessive traits and C57BL/6JSphinx/Sphinx mice die by 12 weeks of age. Coarse mapping placed the mutation in a small interval on chromosome 6, in which no obvious candidate genes were found. The goal of this proposal is to identify the gene carrying the mutation responsible for the described phenotypes. In addition, we intend to characterize the Sphinx phenotype in more detail and to study the interaction between the immune system and tumor cell development. We believe our studies will reveal a novel gene involved in HCC development and provide a new, useful, model system in which to study the interaction between the immune system and hepatocellular tumor formation. PUBLIC HEALTH RELEVANCE: The studies are aimed to identify a yet unknown tumor suppressor gene involved in hepatocellular adenoma/carcinoma development. In addition, using a unique mouse model identified in our laboratory, we aim to study the involvement of the immune system in the pathophysiology of hepatocellular tumor development.

描述（由申请人提供）：肝细胞癌（HCC）占肝脏原发性恶性肿瘤的85%，是世界上第三大癌症相关死亡原因。尽管其病因多种多样，但 HCC 的发展遵循共同的致病特征，即反复性肝损伤导致肝硬化、增生结节的形成和遗传畸变的积累。使用正向遗传学方法，我们鉴定了一种 N-乙基-N-亚硝基脲 (ENU) 诱导的种系突变表型，称为 Sphinx，它会形成自发的多中心肝脏肿瘤。 5周龄时肿瘤形成明显，组织学分析显示组织分化良好且未观察到转移。除了肝细胞肿瘤发展之外，纯合子 Sphinx 小鼠还表现出淋巴细胞发育异常，并且缺乏外周 CD8+ T 和 NK 细胞。这些表型表现为隐性性状，C57BL/6JSphinx/Sphinx 小鼠在 12 周龄时死亡。粗定位将突变定位在6号染色体上的一个小区间内，没有发现明显的候选基因。该提案的目标是鉴定携带导致所描述的表型的突变的基因。此外，我们打算更详细地表征狮身人面像表型，并研究免疫系统与肿瘤细胞发育之间的相互作用。我们相信我们的研究将揭示一种参与 HCC 发展的新基因，并提供一个新的、有用的模型系统来研究免疫系统与肝细胞肿瘤形成之间的相互作用。公共健康相关性：这些研究的目的是确定一种与肝细胞腺瘤/癌发展有关的未知肿瘤抑制基因。此外，利用我们实验室确定的独特小鼠模型，我们旨在研究免疫系统在肝细胞肿瘤发展的病理生理学中的参与。