Wky Rat Genetic Model for Breast Cancer Susceptibility

Wky 大鼠乳腺癌易感性遗传模型

• 批准号: 7842669
• 负责人: MICHAEL N GOULD
• 金额: $ 31.93万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842669
• 关键词: Alkylating Agents; Alleles; Area; Biological; Biological Assay; Breast; Breast Carcinoma; Cancer Etiology; Carcinogens; Cells; Chromosomes; DNA; DNA Resequencing; Data; Disease; Elements; Engineering; Enhancers; Epigenetic Process; Etiology; Functional RNA; Genes; Genetic; Genetic Models; Genomics; Goals; Homologous Gene; Human; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Methods; Modeling; Molecular Conformation; Oncogenes; Organ; Pathway interactions; Phenotype; Predisposition; Progress Reports; Public Health; Quantitative Trait Loci; Rattus; Recombinants; Relative (related person); Risk Marker; Site; T-Lymphocyte; Testing; Transplantation; Woman; cancer risk; cell type; congenic; dimethylbenzanthracene; genetic element; genome wide association study; insight; malignant breast neoplasm; novel; prevent; promoter; public health relevance

DESCRIPTION (provided by applicant): Mcs5 is a mammary carcinoma susceptibility rat quantitative trait locus (QTL) that contains at least three sub-loci (Mcs5a, -5b, and -5c) which contribute to susceptibility and show epistatic interactions with one another. We have shown that Mcs5a, a non-mammary gland cell autonomous locus, is a compound QTL having two interacting elements which differentially control Fbxo10 in T cells. SNPs in human homologues of both of these two elements have each been shown to associate with breast cancer risk in women (n E 12,000). The goal of this continuation proposal is to further study the Mcs5 QTL by characterizing Mcs5c and Mcs5b. The first aim will focus on genetic and biological studies using existing congenic recombinant rat models for the Mcs5c and Mcs5b loci. Both loci will be fine mapped to intervals below 200 Kb. We will also determine if these loci act in a mammary cell autonomous manner. Next, the reduced genomic intervals of Mcs5b and Mcs5c will be annotated by comparing the WKy and WF alleles in order to identify well-defined candidate elements within these loci which underlie their susceptibility phenotypes. The genes and organ/cell type through which each locus exerts its effect on mammary cancer susceptibility will be determined. Focusing on the identified cell type, further genetic and epigenetic differences between the WKy and WF alleles at these two loci will be annotated. Examples of methods to be used include: ChIP-CHIP; chromosome conformation capture assay (3C); resequencing areas identified as potentially functional. Selected candidate loci for Mcs5c and Mcs5b will be validated by producing and characterizing appropriate genetically engineered rat models. This project will identify and characterize novel mammary cancer risk associated alleles. Preliminary data and previous results with Mcs5a suggest that human homologues of these alleles may also contribute to breast cancer risk in humans. Finally, functional studies of the Mcs5c and Mcs5b alleles will define unique pathways involved in the etiology of breast cancer. PUBLIC HEALTH RELEVANCE: This project is directly relative to public health in that it will investigate unique aspects of the genetic component of breast cancer etiology. It is also possible that it will provide risk markers for human breast cancer. Broadly, it will also likely provide new insights for interpretation of the results of genome-wide association studies for common diseases.

描述（由申请人提供）：Mcs5是一种乳腺癌易感性大鼠数量性状基因座（QTL），其包含至少三个亚基因座（Mcs5a、-5b和-5c），这三个亚基因座有助于易感性并显示出彼此上位的相互作用。我们已经证明，非乳腺细胞自主基因座 Mcs5a 是一个复合 QTL，具有两个相互作用的元件，可差异控制 T 细胞中的 Fbxo10。这两种元素的人类同源物中的 SNP 均已被证明与女性患乳腺癌的风险相关 (n E 12,000)。该延续提案的目标是通过表征 Mcs5c 和 Mcs5b 进一步研究 Mcs5 QTL。第一个目标将侧重于利用现有的同源重组大鼠模型进行 Mcs5c 和 Mcs5b 基因座的遗传和生物学研究。两个基因座都将被精细映射到低于 200 Kb 的间隔。我们还将确定这些基因座是否以乳腺细胞自主方式发挥作用。接下来，将通过比较 WKy 和 WF 等位基因来注释 Mcs5b 和 Mcs5c 减少的基因组间隔，以便识别这些基因座内构成其易感性表型的明确候选元件。将确定每个基因座对乳腺癌易感性发挥作用的基因和器官/细胞类型。重点关注已识别的细胞类型，将注释这两个基因座的 WKy 和 WF 等位基因之间的进一步遗传和表观遗传差异。使用的方法的例子包括：ChIP-CHIP；染色体构象捕获测定（3C）；对确定为潜在功能的区域进行重新测序。 Mcs5c 和 Mcs5b 的选定候选基因座将通过生成和表征适当的基因工程大鼠模型进行验证。该项目将鉴定和表征新型乳腺癌风险相关等位基因。 Mcs5a 的初步数据和先前结果表明，这些等位基因的人类同源物也可能会增加人类患乳腺癌的风险。最后，Mcs5c 和 Mcs5b 等位基因的功能研究将确定乳腺癌病因学中涉及的独特途径。公共卫生相关性：该项目与公共卫生直接相关，因为它将研究乳腺癌病因遗传成分的独特方面。它也有可能为人类乳腺癌提供风险标记。从广义上讲，它还可能为解释常见疾病的全基因组关联研究结果提供新的见解。