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: 8507660
• 负责人: Linda D Siracusa
• 金额: $ 15.84万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507660
• 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.

描述（由申请人提供）：寻找影响癌症易感性或抗性的基因一直是科学界的一项重大事业。美国每年有数以万计的人受到小肠癌和结直肠癌 (CRC) 的影响。尽管环境因素在疾病病因学中发挥着重要作用，但揭示潜在的遗传因素对于风险评估以及制定预防措施和新的治疗方法至关重要。家族性腺瘤性息肉病 (FAP) 中的腺瘤性息肉病 (APC) 肿瘤抑制基因发生突变，这是一种遗传性疾病，使个体容易在肠道中形成息肉，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。携带 APC 基因 (ApcMin) 鼠同源物突变的小鼠的遗传背景对于肿瘤表型的表现至关重要，因为近交系对息肉病的易感性各不相同。尽管复杂的性状分析已经确定了改变 ApcMin/+ 小鼠肠道肿瘤数量和大小、乳腺肿瘤发育和辐射诱导的腺瘤多样性的位点，但迄今为止，已确定的基因还不到少数。有人认为，多位点相互作用可能是修饰基因难以找到的原因之一。为了检测表型的变化，可能必须同时改变通路中的几个基因。我们选择采用的方法不仅可以解释单基因座效应，还可以解释受多基因座遗传影响的表型。与利用小鼠品系之间多样性的传统数量性状位点（QTL）研究不同，我们将利用密切相关的近交品系之间的遗传相似性来证明这种替代方法在发现影响肿瘤表型的基因方面的有用性。我们最近发现，C57BL/6J (B6) 与密切相关的品系杂交产生的 F1 ApcMin/+ 后代比其 B6 亲本显着改变了息肉发育的易感性。我们将结合经典遗传学、分子工具和计算资源来识别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位点，而且是牢固地建立这种替代方法来优化复杂性状筛选并加快识别影响肿瘤发生易感性或抗性的致病基因的过程。