Identification and Characterization of a Endogenous EGFR Regulatory Locus in Xiphophorus Genome

剑尾鱼基因组中内源 EGFR 调节位点的鉴定和表征

• 批准号: 10296895
• 负责人: Yuan Lu
• 金额: $ 45.14万
• 依托单位: TEXAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296895
• 关键词: Automobile Driving; Backcrossings; Benign; Biological Models; Book Chapters; Cancer Cell Growth; Cancer Etiology; Candidate Disease Gene; Cell Death; Cell Proliferation; Cell Survival; Cetuximab; Chromosome 5; Chromosome Mapping; Code; Development; Doctor of Philosophy; EGFR Protein Overexpression; EGFR gene; Elements; Enrollment; Epidermal Growth Factor Receptor; Exhibits; Fc Receptor; Fishes; Genes; Genetic Models; Genome; Goals; Human; Hybrids; Impairment; Interview; Journals; Knock-out; Knowledge; Lead; Ligand Binding; Malignant Neoplasms; Medicine; Membrane; Methods; Molecular; Molecular Target; Monoclonal Antibodies; Mus; Mutation; Names; Oncogenes; Oncogenic; Oryziinae; Pathway interactions; Patients; Peer Review; Penetrance; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Platyfish; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Regulator Genes; Relapse; Research; Resistance; Resistance development; Signal Pathway; Signal Transduction; Students; Therapeutic; Transgenic Organisms; Tyrosine Kinase Inhibitor; Universities; Xiphophorus; cancer cell; cancer therapy; cancer type; carcinogenesis; cell type; clinical application; design; dimer; disorder control; genetic analysis; genetic element; genomic locus; inhibitor/antagonist; melanomagenesis; mutant; next generation; novel; novel therapeutic intervention; overexpression; posters; programs; response; segregation; small molecule; treatment strategy; tumor; tumorigenesis

Project Summary: The epidermal growth factor receptor (EGFR) is a leading oncogene firmly associated with many types of cancer. Both anti-EGFR small molecules and monoclonal antibodies have been developed to block its kinase activity for cancer treatment. However, innate and acquired resistance are frequently observed in clinical application. Such observations significantly limit anti-EGFR medicines usage, and also challenge current knowledge of EGFR-driver cancer. Therefore, it is necessary to study the relationship between EGFR and cancer from a different angle, with different research strategy. Xiphophorus maculatus encodes a mutant, autonomous, dysregulated and oncogenic EGFR, named xmrk. However, carcinogenesis is only observed in backcross interspecies hybrid between xmrk positive and xmrk-null Xiphophorus species, or when xmrk is ectopically expressed in non-Xiphophorus model system (e.g., medaka, murine). These suggest that X. maculatus genome also encode a regulator gene that may co-evolved with xmrk and is able to suppressing its oncogenic activity. Therefore, characterizing how the regulator, termed R(Diff) inhibit xmrk, may lead to novel therapeutic strategy in controlling EGFR. Our recent study has defined the R(Diff) tumor regulatory locus to a 101.7 kbp locus on chromosome 5. This small candidate size and low candidate gene number enables functional and mechanistic studies are impractical. Therefore, this proposal is designed to final determine the R(Diff) locus by examining the following aims: Aim 1: We will characterize all expressed but unannotated genetic elements, in addition to the known coding genes, within the newly identified candidate R(Diff) locus, to fully annotate the R(Diff) locus. Aim 2: We will determine the gene/element(s) carrying R(Diff) activity by performing gene knock-out in non-tumor-bearing Xiphophorus fish, tumor-bearing hybrids, and tumor-bearing transgenic medaka. Aim 3: We will profile xmrk and R(Diff) candidates, as well as phenotypes of several Xiphophorus hybrids, to define R(Diff) by association of candidate sequence with varied phenotypes.

项目概要： 表皮生长因子受体 (EGFR) 是公认的主要致癌基因 与多种癌症有关。抗 EGFR 小分子和 单克隆抗体已被开发来阻断其激酶活性以治疗癌症 治疗。然而，先天性和获得性抵抗经常在 临床应用。这些观察结果极大地限制了抗 EGFR 药物 的使用，也挑战了当前对 EGFR 驱动癌症的认识。所以， 有必要从一个角度研究EGFR与癌症的关系 不同的角度，有不同的研究策略。 斑剑鱼编码一种突变体、自主性、失调性和 致癌EGFR，命名为xmrk。然而，仅在以下情况下观察到致癌作用： xmrk 阳性和 xmrk 无效剑尾鱼之间的回交种间杂交 种，或当 xmrk 在非剑尾鱼模型系统中异位表达时 （例如，青鳉、鼠科动物）。这些表明 X. maculatus 基因组还编码 可能与 xmrk 共同进化并能够抑制其的调节基因 致癌活性。因此，描述调节器的特性，称为 R(Diff) 抑制xmrk，可能会导致控制EGFR的新治疗策略。 我们最近的研究将 R(Diff) 肿瘤调控位点定义为 101.7 kbp 5 号染色体上的位点。候选基因尺寸小，候选基因低 数量使得功能和机制研究是不切实际的。所以， 该提案旨在通过检查 以下目标： 目标 1：我们将表征所有已表达但未注释的遗传元件， 除了已知的编码基因外，在新确定的候选 R(Diff) 内 轨迹，完整注释 R(Diff) 轨迹。 目标 2：我们将通过以下方式确定携带 R(Diff) 活性的基因/元件： 对非荷瘤剑鱼、荷瘤鱼进行基因敲除 杂交种和携带肿瘤的转基因青鳉。 目标 3：我们将分析 xmrk 和 R(Diff) 候选者，以及表型 几个Xiphophorus杂种，通过候选者的关联来定义R(Diff) 具有不同表型的序列。

项目成果

Global assessment of organ specific basal gene expression over a diurnal cycle with analyses of gene copies exhibiting cyclic expression patterns.

• DOI: 10.1186/s12864-020-07202-9
• 发表时间: 2020-11-11
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Lu Y;Boswell M;Boswell W;Salinas RY;Savage M;Reyes J;Walter S;Marks R;Gonzalez T;Medrano G;Warren WC;Schartl M;Walter RB
• 通讯作者: Walter RB