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: 8258804
• 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/8258804
• 关键词: 2' -Deoxythymidine; 3-Dimensional; Acquired Immunodeficiency Syndrome; Adverse effects; Affect; Animal Model; Anti-Retroviral Agents; Area; Atrophic; Award; Basic Science; Biological Models; Biology; Catalytic Domain; Cell Aging; Cell Culture Techniques; Cell Proliferation; Cell division; Cells; Clinical Sciences; DNA; DNA Repair; DNA lesion; Doctor of Philosophy; Double Strand Break Repair; Enzymes; Epithelial; Epithelial Cells; Erythema Multiforme; Exhibits; Family; Frequencies; Genetic; Goals; Grant; HIV; Hairy Leukoplakia; Health; Highly Active Antiretroviral Therapy; Human; 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; 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; immortalized cell; in vivo; inhibitor/antagonist; keratinocyte; member; monolayer; novel; novel strategies; oral cavity epithelium; oral fibroblast; oral wart; premature; prevent; professor; programs; regenerative; 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UCLA牙科学院助理教授Mo Kwan Kang的独立科学家奖（K02）的申请。 Kang博士研究计划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）患者的口腔粘膜健康。他的目标是通过开发新的方法来实现这些目标，以防止抗逆转录病毒疗法（ART）的口腔粘膜并发症。 Kang博士最近获得了新的R01赠款，以阐明艺术对人口腔上皮中端粒酶功能的影响。这是Kang博士的一个新研究领域，他的过去研究专注于使用正常的人类口服角质形成细胞（NHOK）作为模型系统的口服上皮生物学。当前K02应用的目的是通过（1）获得HIV和AIDS的基本和临床科学的新知识来扩展Kang博士的当前研究，（2）建立口腔上皮的3维细胞培养模型系统以增强其正在进行的和未来的研究，以及（3）研究RTIS对人类或人类或epithem epithium in vim ins Alal或Alal epithium的影响。研究计划将检验中心假设：RTIS在NHOK中抑制端粒酶抑制，导致口服上皮细胞再生能力的降低以及与HIV+患者的长期服用相关的口服上皮和不良口服粘膜并发症。为了检验这一假设，康博士提出了三个具体目的：（1）确定暴露于RTI的NHOK中的端粒酶活性，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）研究氮化噻噻替氨酸（AZT）对表达外源端粒酶的NHOK表型改变或获得增强的复制潜力的作用。目的1和2将研究RTI在口服上皮中的详细表型和遗传作用。 AIM 3将确定增加具有增强复制电势的细胞的细胞端粒酶活性和/或“启动”是否可以防止AZT的不良表型效应。该项目的结果将用于开发新型的辅助疗法，以防止HIV+患者长期服用抗逆转录病毒药物的口腔粘膜并发症。这将实现Kang博士研究的最终目标，以增强受艾滋病毒和艾滋病影响的患者的口腔粘膜健康。