The squamocolumnar junction and cervical cancer

鳞柱状交界处与宫颈癌

基本信息

批准号：
8429895
负责人：
Christopher Paul Crum
金额：
$ 25.9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-05 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429895
关键词：
Address Adult Animal Model Antibodies Barrett Esophagus Biological Markers Biology Cancer Etiology Cell Culture Techniques Cells Cervical Cervical Intraepithelial Neoplasia Cervix Neoplasms Cervix Uteri Characteristics Classification Cloning Collaborations Columnar Epithelium Development Environment Epithelial Attachment Epithelium Excision Gene Expression Profile Genes Genome Geography Glandular Neoplasms Goals Grant Human Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Immunophenotyping In Vitro Individual Intercellular Junctions Investigation Link Malignant Neoplasms Malignant neoplasm of cervix uteri Maps Methods Modeling Molecular Profiling Molecular Target Mus Natural regeneration Oncogenes Pathogenesis Phenotype Population Proteins Relative (related person)Research Research Personnel Risk Role Squamous Epithelium Stem cells Testing Transgenic Animals Transgenic Mice Virus adjudicate base cancer cell cancer prevention carcinogenesis design drug discovery genetic pedigree human disease human papilloma virus oncogene in vitro Assay in vivo insight mouse model neoplastic novel novel therapeutics pre-clinical promoter prospective public health relevance reproductive tumor

项目摘要

DESCRIPTION (provided by applicant): This project is based on the discovery of a specific cell population in the uterine cervix that the investigators propose to be the target of cancer causing human papillomaviruses (HPV) and the origin of cervical cancer. These cells are located at the squamo-columnar (S-C) junction of the cervix and their share attributes with preinvasive and invasive HPV-associated cervical neoplasms links support their role as progenitor cells. This project is designed to expand this investigation to accomplish three tasks. The first is to clarify the biologic differences of early cervical precancers with S-C junction specific attributes to better define the parameters that increase the empirical risk of eventually developing invasive cancer. Understanding these differences will permit a more precise classification of cervical precancers and reduce the likelihood of over-treatment and its reproductive sequelae. A related goal is to map the geography of these specialized S-C junction cells in the cervix to determine its influence on origin and successful removal of precancers. The second task is to grow these S-C junction cells in culture and determine both how they differentiate and if they express unique biomarkers relative to their surrounding cellular environment. Because the S-C junction is vulnerable to cancer causing HPV infections, these biomarkers could be exploited to devise novel therapies to selectively remove the S-C junction cells preemptively (for cancer prevention) via targeted therapy. The third task is to generate a transgenic animal model (mouse) in which a precise mimic of human cervical cancer could be generated at the S-C junction by introducing carcinogenic HPV-related oncogenes. Such models do not currently exist and their successful development could be an important advance in the creation of mouse models of human cervical cancer that could be used to test new therapeutics.

描述（由申请人提供）：该项目基于子宫颈中特定细胞群的发现，研究人员认为该细胞群是致癌人乳头瘤病毒（HPV）的靶标和宫颈癌的起源。这些细胞位于宫颈鳞柱状 (S-C) 交界处，它们与侵袭前和侵袭性 HPV 相关宫颈肿瘤的共同属性支持了它们作为祖细胞的作用。该项目旨在扩大调查范围以完成三项任务。首先是阐明具有 S-C 连接特异性属性的早期宫颈癌前病变的生物学差异，以更好地定义增加最终发展为浸润性癌症的经验风险的参数。了解这些差异将有助于对宫颈癌前病变进行更精确的分类，并减少过度治疗及其生殖后遗症的可能性。一个相关的目标是绘制子宫颈中这些特殊 S-C 连接细胞的地理分布图，以确定其对癌前病变起源和成功去除的影响。第二个任务是在培养物中培养这些 S-C 连接细胞，并确定它们如何分化以及它们是否表达相对于周围细胞环境的独特生物标志物。由于 S-C 连接很容易受到引起 HPV 感染的癌症的影响，因此可以利用这些生物标志物来设计新的疗法，通过靶向治疗选择性地先发制人地去除 S-C 连接细胞（用于预防癌症）。第三个任务是生成转基因动物模型（小鼠），通过引入致癌的 HPV 相关癌基因，可以在 S-C 连接处生成人类宫颈癌的精确模拟物。目前尚不存在此类模型，它们的成功开发可能是创建可用于测试新疗法的人类宫颈癌小鼠模型的重要进展。