Phenotypic and genetic effects of antiretroviral therapy on human oral epithelium

描述(由申请人提供)：这是加州大学洛杉矶分校牙科学院助理教授莫群康博士申请的独立科学家奖(K02)。康博士研究项目的长期目标是促进受人类免疫缺陷病毒(HIV)感染和获得性免疫缺陷综合征(AIDS)影响的患者的口腔粘膜健康。他的目标是通过开发新的方法来预防抗逆转录病毒疗法(ART)的口腔粘膜并发症来实现这些目标。Kang博士最近获得了新的R01奖金，以阐明ART对人类口腔上皮细胞端粒酶功能的影响。这对康博士来说是一个新的研究领域，他过去的研究重点是口腔上皮生物学，使用正常的人类口腔角质形成细胞(NHOK)作为模型系统。目前K02应用的目的是通过(1)获得艾滋病毒和艾滋病的基础和临床科学方面的新知识，(2)建立口腔上皮三维细胞培养模型系统，以加强他正在进行的和未来的研究，以及(3)建立一个动物模型，利用该模型研究RTI对活体人类口腔上皮的影响，从而扩展K02博士目前的研究范围。该研究计划将检验中心假设：RTI抑制NHOK中的端粒酶是导致HIV患者长期服用ART导致口腔上皮再生能力减弱和不良口腔粘膜并发症的原因。为了验证这一假说，康博士提出了三个具体目标：(1)确定RTI暴露对NHOK细胞端粒酶活性、端粒状态和细胞表型变化的影响；(2)确定RTI对NHOK细胞DNA修复活性、突变频率和遗传完整性的影响；(3)研究叠氮胸苷(AZT)对表达外源性端粒酶或获得增强复制潜力的NHOK细胞表型变化的影响。目标1和目标2将研究口腔上皮中RTI的详细表型和遗传效应。目的3将确定增强细胞端粒酶活性和/或使细胞具有增强的复制能力是否可以防止AZT的不利表型效应。该项目的成果将用于开发新的辅助疗法，以预防艾滋病毒患者长期服用抗逆转录病毒药物引起的口腔粘膜并发症。这将实现康博士研究的最终目标，即提高受艾滋病毒和艾滋病影响的患者的口腔粘膜健康。

DESCRIPTION (provided by applicant): This is an application for the Independent Scientist Award (K02) from Mo Kwan Kang, DOS, PhD, Assistant Professor at the UCLA School of Dentistry. The long-term goal of Dr. Kang's research program is to promote oral mucosal health in the patients affected by human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). He aims to achieve these goals by developing novel approaches to prevent the oral mucosal complications of antiretroviral therapies (ART). Dr. Kang has recently been awarded a new R01 grant to elucidate the effects of ART on telomerase function in human oral epithelium. This is a new area of investigation for Dr. Kang, whose past research has focused on oral epithelial biology using normal human oral keratinocytes (NHOK) as a model system. The purpose of the current K02 application is to extend Dr. Kang's current research by (1) gaining new knowledge in the basic and clinical sciences of HIV and AIDS, (2) establishing the 3-dimensional cell culture model system of oral epithelium to enhance his ongoing and future research, and (3) developing an animal model with which to study the effects of RTIs on human oral epithelium in vivo. The research plan will test the central hypothesis: 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 ART in HIV+ patients. To test this hypothesis, Dr. Kang proposed three Specific Aims: (1) to determine the telomerase activity, telomeric status, and cellular phenotypic alteration in NHOK exposed to RTIs; (2) to determine the effects of RTI on the DNA repair activities, mutation frequency, and genetic integrity in NHOK; and (3) to investigate the effects of azidothymidine (AZT) on phenotypic alterations in NHOK expressing exogenous telomerase or acquiring enhanced replication potential. The Aims 1 and 2 will investigate detailed phenotypic and genetic effects of RTIs in oral epithelium. Aim 3 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 to develop novel adjunctive therapies to prevent the oral mucosal complications of long-term administration of antiretroviral medications in HIV+ patients. This will fulfill the ultimate objectives of Dr. Kang's research to enhance the oral mucosal health of the patients affected by HIV and AIDS.