Use of Closely Related Inbred Strains to Identify Modifier Loci of Tumorigenesis

使用密切相关的近交株来鉴定肿瘤发生的修饰位点

• 批准号: 8356584
• 负责人: Linda D Siracusa
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356584
• 关键词: APC gene; Accounting; Adenomatous Polyposis Coli; Adopted; Affect; Alleles; Backcrossings; Bioinformatics; Candidate Disease Gene; Code; Colon; Colorectal Cancer; Columbidae; Communities; Complex; DNA Sequence Analysis; Development; Disease; Early Diagnosis; Environmental Risk Factor; Etiology; Evaluation; Foundations; Functional RNA; Gene Proteins; Gene-Modified; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Goals; Homologous Gene; Human; Hybrids; Inborn Genetic Diseases; Inbred Strain; Individual; Intestinal Cancer; Intestinal Neoplasms; Intestinal Polyps; Intestines; Knowledge; Laboratories; Life; Location; Malignant Neoplasms; Mammary Neoplasms; Measures; Methods; Molecular Genetics; Mouse Strains; Mus; Mutate; Mutation; Parents; Pathway interactions; Patients; Persons; Phenotype; Play; Point Mutation; Polyps; Predisposition; Process; Proteins; Quantitative Trait Loci; Radiation; Research; Resistance; Risk; Risk Assessment; Role; Single Nucleotide Polymorphism; Small Intestines; Therapeutic; Transcript; Tumor Suppressor Genes; United States; Variant; adenoma; aged; computing resources; design; gene discovery; gene function; genetic variant; insertion/deletion mutation; malignant small intestine tumor; mouse model; mutant; novel; novel therapeutics; offspring; polyposis; prevent; processing speed; tool; trait; treatment strategy; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The quest for genes influencing susceptibility or resistance to cancer has been a major undertaking by the scientific community. Every year tens of thousands of individuals in the United States are affected by small intestine and colorectal cancers (CRC). Although environmental factors play a role in disease etiology, uncovering underlying genetic factors is imperative in risk assessment and for developing preventative measures and novel therapeutics for treatment. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), an inherited disorder that predisposes individuals to developing polyps in their intestinal tract and which eventually leads to cancer. Mouse models have served as valuable tools to study the process of tumorigenesis. The genetic background of mice carrying a mutation in the murine homolog of the APC gene (ApcMin) is critical to the manifestation of tumor phenotypes, as inbred strains vary in their susceptibility to polyposis. Although complex trait analyses have identified loci tha modify intestinal tumor number and size, mammary tumor development, and radiation-induced adenoma multiplicity in ApcMin/+ mice, less than a handful of genes have been identified to date. It has been suggested that multiple-locus interactions may be one reason that modifier genes are difficult to find. Several genes in a pathway may have to be altered concurrently in order for a shift in phenotype to be detected. We chose to adopt an approach that will account for not only single-locus effects, but phenotypes influenced by multiple-loci inheritance as well. Unlike traditional quantitative trait loci (QTL) studies that exploit the diversity among mouse strains, we will take advantage of genetic similarities between closely-related inbred strains to demonstrate the usefulness of this alternative approach to discover genes that influence tumor phenotypes. We recently found that F1 ApcMin/+ offspring from crosses between C57BL/6J (B6) and closely-related strains have significantly altered susceptibilities to developing polyps than their B6 parents. We will use a combination of classical genetics, molecular tools, and computational resources to identify biomolecular pathways that modulate intestinal tumorigenesis. Our goal is not only to identify new modifier loci, but also to firmly establish thi alternative approach to optimize complex trait screens and speed the process of identification of causative genes influencing susceptibility or resistance to tumorigenesis. PUBLIC HEALTH RELEVANCE: One form of a gene can make a person susceptible to cancer, while another form of the same gene can make another person resistant to a life-threatening cancer. This research is designed to discover genes that function to protect against the development of tumors in the small intestine and colon. A second goal is to establish methods to quickly and efficiently identify these genes and pathways. With this knowledge, research can move towards developing novel preventative options for people at risk and potential therapeutic options for patients with cancer.

描述（由申请人提供）：科学界的一项重大承诺。每年，美国成千上万的人都会受到小肠和大肠癌（CRC）的影响。尽管环境因素在疾病病因中起作用，但在风险评估以及制定预防措施和新型治疗疗法中，揭示潜在的遗传因素至关重要。腺瘤性息肉病（APC）肿瘤抑制基因在家族性腺瘤性息肉病（FAP）中突变，这是一种遗传性疾病，一种使人容易在其肠道中发展息肉，并最终导致癌症。小鼠模型已成为研究肿瘤发生过程的宝贵工具。在APC基因（APCMIN）的鼠同源物中携带突变的小鼠的遗传背景对于肿瘤表型的表现至关重要，因为近交菌株对息肉病的敏感性有所不同。尽管复杂的性状分析已经鉴定出肠道肿瘤的数量和大小，乳腺肿瘤的发育和辐射诱导的APCMIN/+小鼠的腺瘤多样性，但迄今为止已经识别出少数基因。已经提出，难以找到修饰的基因可能是多个基因相互作用的原因之一。为了检测表型的转移，可能必须同时改变途径中的几个基因。我们选择采用一种方法，不仅可以解释单位效应，而且还会解释受多Loci遗传影响的表型。与传统的定量性状基因座（QTL）研究相比，利用小鼠菌株之间的多样性的研究，我们将利用与紧密相关的近交菌株之间的遗传相似性，以证明这种替代方法的有用性来发现影响肿瘤表型的基因。我们最近发现，与B6父母相比，F1 APCMIN/+后代来自C57BL/6J（B6）和密切相关菌株之间的十字架和密切相关的菌株的敏感性明显改变。我们将使用经典遗传学，分子工具和计算资源的组合来鉴定调节肠道肿瘤发生的生物分子途径。我们的目标不仅是识别新的修饰基因座，而且还牢固地建立了这种替代方法来优化复杂性状筛选并加快影响易感性或对肿瘤发生抗性的病因基因的鉴定过程。 公共卫生相关性：一种基因的一种形式可以使一个人容易患癌症，而同一基因的另一种形式可以使另一个人抵抗危及生命的癌症。这项研究旨在发现能够防止小肠和结肠中肿瘤发展的基因。第二个目标是建立快速有效地识别这些基因和途径的方法。有了这些知识，研究可以为有风险的人和癌症患者的潜在治疗选择开发新的预防选择。