课题基金 / 基金详情

(PQ1) Characterization of Premalignant Fields in a Murine Model of Head and Neck and Esophageal Cancers

(PQ1) Characterization of Premalignant Fields in a Murine Model of Head and Neck and Esophageal Cancers
(PQ1) 头颈癌和食管癌小鼠模型癌前区域的表征
批准号:
9903826
负责人:
LORRAINE J GUDAS
金额:
$9.7万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-23 至 2021-05-31

项目摘要

项目成果

LORRAINE J GUDAS的其他基金

相似基金

相关文献

中文摘要
翻译
摘要来自母体r01 (ca205258)
英文摘要
ABSTRACT FROM PARENT R01 (CA205258) Head and neck squamous cell carcinoma (HNSCC) occurs in the oral cavity, oropharynx, and larynx and is the 6th leading cancer in terms of incidence, affecting ~600,000 patients throughout the world. Esophageal squamous cell carcinoma (ESCC) is also quite common, with 17,000 new cases estimated in 2015 in the USA. Despite intensive treatment that generally combines surgery, radiation, and chemotherapy, HNSCCs and ESCCs relapse frequently and have poor long-term survival rates. Here we propose to use an approach using lineage-tracing to test the hypothesis that carcinogens cause early molecular changes in some progenitor/stem cells that reduce the diversity of the stem/progenitor cell population and subsequently result in both field cancerization and tumor formation in our murine HNSCC and ESCC carcinogenesis models. Thus, in this proposal we address one of the “Provocative Questions” of RFA-CA-15-008: For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors? We will answer this question by performing two specific aims. Briefly, we will use doubly transgenic Keratin14/cre-ERTAM; Rosa26-lacZ mice to permanently mark individual normal stem/ progenitor cells and their progeny in the oral cavity and esophagus. Cre-dependent recombination will be activated only in cells that express K14 at the time of addition of tamoxifen (Tam), which is required for the cre-ERTAM protein to be active, giving us both temporal control and cell type-specific control over the cre recombinase activity and allowing us to follow the fates of these stem/ progenitor cells and their progeny over time. In Specific Aim (1), we will perform lineage-tracing, whole genome RNA-seq analyses, and whole exome DNA sequencing of these permanently marked lacZ+ “clones” of cells derived from individual, epithelial progenitor/stem cells during treatment with the carcinogen 4-nitroquinoline oxide (4-NQO), a tobacco surrogate, in the drinking water. This aim will delineate early molecular changes that occur in (a) the oral epithelium, and (b) the esophageal epithelium in a mouse model that very closely reflects human HNSCC and esophageal SCC development. We will also measure some key epigenetic changes. In Specific Aim (2) we will discern the key molecular changes that occur much later in the carcinogenesis process, when visible SCCs are present, by performing lineage tracing, whole genome RNA-seq analyses, and whole exome DNA sequencing of permanently marked “clones” of cells, derived from individual epithelial progenitor/ stem cells (both HNSCCs & ESCCs). In Aim (2) we will also compare tumors to clones of cells with normal morphology that are present near SCCs in “normal appearing” epithelial mucosa. Completion of these aims will define genetic and epigenetic changes that underlie ‘field cancerization,’ providing much new information about critical, early molecular changes in HNSCC and esophageal carcinogenesis that could be exploited to develop cancer chemopreventive drugs.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
CD 1530, an RAR Gamma Agonist for Oral Cavity Squamous Cell Carcinoma Prevention
Gene Nutrient Interactions in Kidney Function
Uncovering the Role of Retinoic Acid Receptor Beta in Alcoholic Liver Diseases
Uncovering the Role of Retinoic Acid Receptor Beta in Alcoholic Liver Diseases
海外基金