Effects of Antiretroviral Therapy on Telomerase Function in Human Oral Epithelium

抗逆转录病毒治疗对人口腔上皮端粒酶功能的影响

• 批准号: 7765482
• 负责人: Mo K. Kang
• 金额: $ 34.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765482
• 关键词: 2' -Deoxythymidine; Acquired Immunodeficiency Syndrome; Adverse effects; Atrophic; Biological Process; Catalytic Domain; Cell Aging; Cell Proliferation; Cell division; Cells; DNA; DNA Repair; DNA lesion; Development; Double Strand Break Repair; Epithelial; Epithelial Cells; Erythema Multiforme; Exhibits; Family; Frequencies; Genetic; Genome; Goals; HIV; Hairy Leukoplakia; Highly Active Antiretroviral Therapy; Human; In Vitro; Individual; Laboratories; Laboratory Finding; Lead; Length; Maintenance; Mediating; Molecular; Mutation; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Outcome; Patients; Population; Prevention; Proliferating; Proteins; RNA; RNA-Directed DNA Polymerase; Recurrence; Reporting; Research Personnel; Retroviridae; Reverse Transcriptase Inhibitors; Role; Somatic Cell; Stem cells; Stratification; Telomerase; Telomerase RNA Component; Telomerase inhibition; Telomere Shortening; Testing; Ulcer; Virus Diseases; anti-cancer therapeutic; antiretroviral therapy; cancer cell; enzyme activity; human TERT protein; in vivo; keratinocyte; member; monolayer; novel; oral cavity epithelium; oral fibroblast; oral wart; premature; prevent; programs; regenerative; senescence; telomere

DESCRIPTION (provided by applicant): The long-term goal of this project is to reduce or reverse the oral complications of highly active antiretroviral therapy (HAART) in patients infected with the human immunodeficiency virus (HIV). Although the oral manifestations of HIV infection have significantly decreased after the introduction of HAART, several adverse effects have also been reported in the oral mucosa, including recurrent oral ulceration, epithelial atrophy, erythema multiforme, epithelial desquamation, eruptive chielitis, and multiple oral warts. The purpose of the current application is to elucidate the effects of telomerase inhibition by reverse transcriptase inhibitors (RTIs) in mediating the side effects of HAART. Telomerase is a cellular reverse transcriptase with at least two distinct biological functions in (1) synthesis of telomere DNA and (2) maintenance of genome integrity. Our laboratory found remarkably high level of telomerase activity in normal human oral keratinocytes (NHOK) derived from oral epithelium. Telomerase activity in NHOK is specifically associated with actively proliferating cells and is completely lost during cellular senescence. Importantly, telomerase activity can be effectively inhibited by several RTIs commonly used as HAART. The central hypothesis of this proposal is that telomerase inhibition in NHOK by RTIs is responsible for the diminution of regenerative capacity of the oral epithelium and adverse oral mucosal complications associated with long-term administration of HAART in HIV+ patients. To test our hypothesis, we propose three Specific Aims: (1) to determine the telomerase activity, telomeric status, and cellular phenotypic alterations in NHOK exposed to RTIs in vitro and in cells derived from HIV+ patients with and without HAART; (2) to determine the effects of RTI/HAART on the DNA repair activities, mutation frequency, and genetic integrity in NHOK; and (3) to investigate the effects of AZT on phenotypic alterations in NHOK expressing exogenous telomerase or acquiring enhanced replication potential. The aims 1 and 2 will investigate the detailed phenotypic and genetic effects of RTI/HAART in oral epithelium. In aim 3, we will determine whether augmenting cellular telomerase activity and/or "priming" the cells with enhanced replicative potential can prevent the adverse phenotypic effects of AZT. The outcome of this project will be used for prevention and management of oral manifestations of HIV infection and the acquired immunodeficiency syndrome (AIDS) by reducing the negative effects of HAART.

描述（由申请人提供）：该项目的长期目标是减少或扭转感染人类免疫缺陷病毒（HIV）患者的高活性抗逆转录病毒疗法（HAART）的口服并发症。尽管引入HAART后，HIV感染的口服表现显着降低，但在口服粘膜中也有几种不良反应，包括复发性口腔溃疡，上皮性萎缩，多形，多形，上皮性脱落，脱皮的chielitive chielitis，chielitis炎和多种口腔摔跤。当前应用的目的是阐明逆转录酶抑制剂（RTI）在介导HAART的副作用中抑制端粒酶抑制作用。端粒酶是一种细胞逆转录酶，在（1）端粒DNA合成和（2）维持基因组完整性时具有至少两个不同的生物学功能。我们的实验室发现源自口服上皮的正常人口腔角质形成细胞（NHOK）中的端粒酶活性非常高。 NHOK中的端粒酶活性与主动增殖细胞特别相关，并且在细胞衰老过程中完全丢失。重要的是，通常用作HAART的几种RTI可以有效抑制端粒酶活性。该提案的中心假设是，RTIS中NHOK中的端粒酶抑制是导致口服上皮的再生能力和与HAART在HIV+患者长期给药有关的不良口服粘膜并发症的再生能力的降低。为了检验我们的假设，我们提出了三个具体目的：（1）确定端粒酶活性，端粒状态和细胞表型改变在体外暴露于RTI的NHOK和来自HAART和没有HAART的HIV+患者的细胞中； （2）确定RTI/HAART对NHOK中DNA修复活性，突变频率和遗传完整性的影响； （3）研究AZT对表达外源端粒酶的NHOK表型改变的影响或获得增强的复制潜力。目的1和2将研究RTI/HAART在口腔上皮中的详细表型和遗传作用。在AIM 3中，我们将确定增强细胞端粒酶活性和/或“启动”具有增强势能的细胞是否可以防止AZT的不良表型作用。该项目的结果将用于预防和管理HIV感染的口服表现，并通过减少HAART的负面影响来预防HIV感染的口服表现以及获得的免疫缺陷综合征（AIDS）。