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.

项目总结:

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