HPV, Genetic Instability & Oral Cancer
HPV, Genetic Instability & Oral Cancer
批准号:
6751554
负责人:
NO-HEE PARK
金额:
$24.02万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-08-01 至 2006-06-30
关键词:
DNA damageDNA repairathymic mousecell transformationepitheliumgene expressiongene frequencygene induction /repressiongene mutationhuman papillomavirushuman tissuekeratinocytemethylguanine DNA methyltransferaseneoplasm /cancer geneticsnorthern blottingsoncogenesoral pharyngeal neoplasmp53 gene /proteinpolymerase chain reactionpreneoplastic stateribozymesscintillation countertissue /cell cultureviral carcinogenesisvirus related neoplasm /cancerwestern blottings
中文摘要
描述:(申请人提供)频繁感染人
口腔中的乳头状瘤病毒(HPV)已注意到在HIV免疫功能低下的
儿童和成人。艾滋病毒感染者更容易受到感染
多种HPV亚型,包括16型和18型。这些“高危”HPV
与恶性口腔癌的发展密切相关:
病毒DNA经常在口腔癌细胞和组织中发现。此外,委员会认为,
用克隆的“高表达”转染正常人口腔角质形成细胞(NHOK)
风险”HPV基因组使这些细胞永生,这些细胞可以完全转化为
转化的细胞暴露在化学致癌物中。由于(1)相同
化学致癌物不能转化NHOK细胞和(2)基因组丢失
完整性是肿瘤细胞的标志,“高危型”HPV必须发挥重要作用。
在NHOK细胞恶性转化中的关键作用,
细胞维持基因组完整性的能力。保持基因组完整性
通过不断修复DNA损伤;因此,DNA修复的干扰导致
突变,其最终诱导细胞的恶性转化。的
该项目的中心假设是,感染NHOK细胞的“高
“危险”HPV癌基因破坏DNA修复;抑制HPV癌基因
表达允许癌前人类口腔上皮细胞高表达
风险”HPV癌基因恢复其DNA修复活性和基因组
完整为了检验这一假设,申请人提出以下建议
具体目的:(1)确定基础和遗传毒性剂诱导的DNA
NHOK细胞,用HPV-16基因组转染的HOK细胞,
和肿瘤前口腔上皮细胞(来源于病变活检)
表达“高危”HPV;(2)研究HPV-16癌基因的作用
对NHOK细胞的基础和遗传毒性试剂诱导的DNA修复活性的影响;以及
(3)研究高危型HPV核酶对DNA修复活性的影响
次黄嘌呤磷酸核糖转移酶的突变频率(和突变率)
人口腔上皮细胞癌前和癌后的hprt基因
(表达“高风险”HPV)。申请人
希望回答以下问题:“高危”HPV是否会破坏
修复NHOK细胞中的DNA损伤如果是这样,DNA修复过程是什么?
受损?病毒致癌基因是否是造成这种破坏的原因?如果是这样,
HPV癌基因使p53或pRB失活,
干扰?肿瘤前或肿瘤细胞(表达“高危”HPV)
来自人类口腔病变活检的DNA具有相同的DNA修复谱
缺陷作为NHOK细胞转染“高风险”HPV基因组?是否
病毒癌基因转录物的破坏恢复了DNA修复活性,
HPV-永生化HOK细胞的基因组完整性,肿瘤前和肿瘤
表达“高危”HPV的人口腔上皮细胞(来自病变活检)
致癌基因?
英文摘要
DESCRIPTION: (Provided by Applicant) Frequent infection with human
papillomavirus (HPV) in the oral cavity has been noted in HIV immunocompromised
children and adults. HIV-infected individuals are more susceptible to infection
with multiple HPV subtypes, including types 16 and 18. These "high risk" HPVs
that are closely associated with development of malignant oral cancer: the
viral DNA is frequently found in oral cancer cells and tissue. Moreover,
transfection of normal human oral keratinocyte (NHOK) cells with cloned "high
risk" HPV genome immortalizes these cells, which can convert to fully
transformed cells when exposed to chemical carcinogens. Since (1) the same
chemical carcinogens cannot transform NHOK cells and (2) the loss of genomic
integrity is the hallmark of neoplastic cells, "high risk" HPV must play a
critical role in the malignant transformation of NHOK cells by disrupting
cells' ability to maintain genomic integrity. Genomic integrity is maintained
by constant repair of DNA damage; thus, disturbance of DNA repair results in
mutations, which ultimately induces malignant transformation of cells. The
central hypothesis of the project is that infection of NHOK cells with "high
risk" HPV oncogenes disrupts DNA repair; and that inhibition of HPV oncogene
expression allows pre-neoplastic human oral epithelial cells expressing high
risk" HPV oncogenes to regain their DNA repair activities and genomic
integrity. To test this hypothesis, the applicants propose the following
specific aims: (1) to determine the basal and genotoxic agent-induced DNA
repair activities of NHOK cells, HOK cells transfected with the HPV-16 genome,
and pre-neoplastic oral epithelial cells (derived from lesion biopsies)
expressing "high risk" HPV; (2) to investigate the effects of HPV-16 oncogenes
on basal and genotoxic agent-induced DNA repair activities of NHOK cells; and
(3) to study the effect of "high risk" HPV ribozymes on DNA repair activities
and mutation frequency (and rate) of hypoxanthine phosphoribosyl transferase
(hprt) gene of pre-neoplastic and neoplastic human oral epithelial cells
(expressing "high risk" HPV) derived from lesion biopsies. The applicants
expect to answer the following questions: Does "high risk" HPV disrupt the
repair of DNA damage in NHOK cells? If so, which DNA repair process is
impaired? Are viral oncogenes responsible for such disruption? If so, is the
inactivation of p53 or pRB by HPV oncogenes solely responsible for the
disruption? Do pre-neoplastic or neoplastic cells (expressing "high risk" HPV)
derived from human oral lesion biopsies have the same spectrum of DNA repair
defects as NHOK cells transfected with "high risk" HPV genome? Does the
disruption of viral oncogene transcripts restore the DNA repair activites and
genomic integrity of HPV-immortalized HOK cells, pre-neoplastic and neoplastic
human oral epithelial cells (from lesion biopsies) expressing "high risk" HPV
oncogenes?
期刊论文(0)
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会议论文
HPV, Genetic Instability & Oral Cancer
-
批准号:6604192
-
项目类别:
-
资助金额:$24.02万
-
财政年份:2001
-
负责人:NO-HEE PARK
-
依托单位:
HPV, Genetic Instability & Oral Cancer
-
批准号:6345366
-
项目类别:
-
资助金额:$24.1万
-
财政年份:2001
-
负责人:NO-HEE PARK
-
依托单位:
HPV, Genetic Instability & Oral Cancer
-
批准号:6920713
-
项目类别:
-
资助金额:$24.02万
-
财政年份:2001
-
负责人:NO-HEE PARK
-
依托单位:
HPV, Genetic Instability & Oral Cancer
-
批准号:6516667
-
项目类别:
-
资助金额:$24.02万
-
财政年份:2001
-
负责人:NO-HEE PARK
-
依托单位:
EXTRAMURAL RESEARCH FACILITIES CONSTRUCTION PROJECTS
-
批准号:6039614
-
项目类别:
-
资助金额:$100.0万
-
财政年份:1999
-
负责人:NO-HEE PARK
-
依托单位:
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
-
批准号:6201791
-
项目类别:
-
资助金额:$20.83万
-
财政年份:1999
-
负责人:NO-HEE PARK
-
依托单位:
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
-
批准号:6104861
-
项目类别:
-
资助金额:$20.22万
-
财政年份:1998
-
负责人:NO-HEE PARK
-
依托单位:
IMMUNOGENE THERAPY FOR ORAL CANCER
-
批准号:2501248
-
项目类别:
-
资助金额:$3.92万
-
财政年份:1998
-
负责人:NO-HEE PARK
-
依托单位:
IMMUNOGENE THERAPY FOR ORAL CANCER
-
批准号:2872162
-
项目类别:
-
资助金额:$3.68万
-
财政年份:1998
-
负责人:NO-HEE PARK
-
依托单位:
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
-
批准号:6238532
-
项目类别:
-
资助金额:$20.08万
-
财政年份:1997
-
负责人:NO-HEE PARK
-
依托单位:
GENES FOR ORAL CARCINOGENESIS
-
批准号:2430136
-
项目类别:
-
资助金额:$3.76万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:2391193
-
项目类别:
-
资助金额:$16.55万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:6175851
-
项目类别:
-
资助金额:$18.67万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
GENES FOR ORAL CARCINOGENESIS
-
批准号:2133128
-
项目类别:
-
资助金额:$3.69万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:2129802
-
项目类别:
-
资助金额:$8.93万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:2683976
-
项目类别:
-
资助金额:$28.45万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:6492741
-
项目类别:
-
资助金额:$13.23万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
UCLA FUNDAMENTAL CLINICAL RESEARCH TRAINING PROGRAM
-
批准号:2896978
-
项目类别:
-
资助金额:$20.14万
-
财政年份:1996
-
负责人:NO-HEE PARK
-
依托单位:
CELL CYCLE, P53, AND DNA REPAIR IN ORAL CARCINOGENESIS
-
批准号:2749342
-
项目类别:
-
资助金额:$20.64万
-
财政年份:1995
-
负责人:NO-HEE PARK
-
依托单位:
CELL CYCLE, P53, AND DNA REPAIR IN ORAL CARCINOGENESIS
-
批准号:2600436
-
项目类别:
-
资助金额:$6.25万
-
财政年份:1995
-
负责人:NO-HEE PARK
-
依托单位:
海外基金