Phenotypic and genetic effects of antiretroviral therapy on human oral epithelium

抗逆转录病毒治疗对人类口腔上皮的表型和遗传影响

• 批准号: 7452738
• 负责人: Mo K. Kang
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452738
• 关键词: 2' -Deoxythymidine; 3-Dimensional; Acquired Immunodeficiency Syndrome; Adverse effects; Affect; Animal Model; Anti-Retroviral Agents; Area; Atrophic; Award; Biological Models; Biology; Catalytic Domain; Cell Aging; Cell Proliferation; Cell division; Cells; Clinical Sciences; Cultured Cells; DNA; DNA Repair; DNA lesion; Doctor of Philosophy; Double Strand Break Repair; Enzymes; Epithelial; Epithelial Cells; Erythema Multiforme; Exhibits; Family; Frequencies; Future; Genetic; Goals; Grant; HIV; Hairy Leukoplakia; Health; Highly Active Antiretroviral Therapy; Human; Immunologic Deficiency Syndromes; In Vitro; Independent Scientist Award; Individual; Investigation; Knowledge; Laboratories; Length; Molecular; Mutation; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Outcome; Patients; Pharmaceutical Preparations; Population; Proliferating; Purpose; RNA; RNA-Directed DNA Polymerase; Reporting; Research; Retroviridae; Reverse Transcriptase Inhibitors; Role; School Dentistry; Somatic Cell; Telomerase; Telomerase RNA Component; Telomerase inhibition; Telomere Shortening; Testing; Ulcer; Virus Diseases; Zidovudine; anti-cancer therapeutic; antiretroviral therapy; cancer cell; enzyme activity; human TERT protein; in vivo; inhibitor/antagonist; keratinocyte; member; monolayer; novel; novel strategies; oral cavity epithelium; oral fibroblast; oral wart; prevent; professor; programs; senescence

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.

描述（由申请人提供）：这是一份来自加州大学洛杉矶分校牙科学院助理教授 Mo Kwan Kang 博士的独立科学家奖 (K02) 申请。康博士研究项目的长期目标是促进人类免疫缺陷病毒（HIV）感染和获得性免疫缺陷综合症（AIDS）患者的口腔粘膜健康。他的目标是通过开发新方法来预防抗逆转录病毒疗法（ART）引起的口腔粘膜并发症，从而实现这些目标。 Kang 博士最近获得了一项新的 R01 资助，以阐明 ART 对人类口腔上皮端粒酶功能的影响。这是 Kang 博士研究的一个新领域，他过去的研究重点是使用正常人口腔角质形成细胞 (NHOK) 作为模型系统的口腔上皮生物学。目前K02申请的目的是通过以下方式扩展康博士目前的研究：(1)获得艾滋病毒和艾滋病基础和临床科学的新知识，(2)建立口腔上皮细胞的3维细胞培养模型系统，以加强他正在进行和未来的研究，以及(3)开发一种动物模型，用于研究RTI在体内对人类口腔上皮细胞的影响。该研究计划将测试中心假设：RTIs 抑制 NHOK 中的端粒酶导致口腔上皮再生能力下降，以及与 HIV+ 患者长期接受 ART 相关的不良口腔粘膜并发症。为了验证这一假设，Kang博士提出了三个具体目标：（1）确定暴露于RTIs的NHOK的端粒酶活性、端粒状态和细胞表型改变； (2) 确定RTI对NHOK中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) 对表达外源端粒酶或获得增强复制潜力的 NHOK 表型改变的影响。目标 1 和 2 将研究口腔上皮细胞中 RTI 的详细表型和遗传效应。目标 3 将确定增强细胞端粒酶活性和/或“启动”具有增强复制潜力的细胞是否可以预防 AZT 的不良表型效应。该项目的成果将用于开发新型辅助疗法，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，即增强艾滋病毒和艾滋病患者的口腔粘膜健康。