Effects of ART on Oral Epithelial Cell Biology

描述（由申请人提供）：人类免疫缺陷病毒（HIV）每年感染数百万人，是世界范围内死亡的主要原因。在没有药物治疗的情况下，通常在感染后10年内死亡。抗逆转录病毒药物的引入大大降低了发病率和死亡率。然而，抗逆转录病毒治疗必须终生服用，其长期影响（如血脂异常、线粒体功能障碍、外分泌病理）直到最近才被认识到。目前缺乏针对抗逆转录病毒治疗对口腔黏膜不良影响的研究。我们的目标是阐明ART对口腔软组织功能的影响，重点是上皮细胞生物学。这一知识对于理解抗逆转录病毒治疗对控制HIV感染者口腔机会性感染的黏膜和上皮至关重要的长期影响是必要的。本研究的一般假设是，选择性抗逆转录病毒药物失调口腔上皮细胞生物学，影响正常的蛋白酶体通路、上皮细胞稳态和先天免疫参数，导致口腔黏膜和上皮细胞对微生物病原体的反应能力发生有害改变。我们的具体目标是：1)研究ART对口腔上皮细胞蛋白酶体-蛋白水解途径的影响；2)确定ART对口腔上皮细胞toll样受体（TLR）信号通路的影响；3)确定ART对口腔上皮细胞分化的影响。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infects millions of humans annually and is a leading cause of death worldwide. In the absence of medical therapy, death usually results within 10 years of infection. The introduction of antiretroviral (ART) drugs has significantly diminished morbidity and mortality. However, ART must be taken throughout life, and the several long term effects (e.g. dyslipidemia, mitochondrial dysfunction, exocrine pathology) have only recently been appreciated. Studies that address the adverse effects of ART on the oral mucosa are lacking. Our goal is to elucidate the effects of ART on the function of oral soft tissues, focusing on epithelial cell biology. This knowledge is a requisite for understanding the long-term implications of ART on the critical importance of the mucosa and epithelium in controlling oral opportunistic infections in HIV infected individuals. The GENERAL HYPOTHESIS of the proposed research is select ART drugs dysregulate oral epithelial cell biology, impacting on normal proteasome pathways, epithelial cell homeostasis, and parameters of innate immunity, resulting in deleterious alternations of the oral mucosa and the epithelial cell's ability to respond to microbial pathogens. Our specific aims are to 1) examine the effect of ART on the proteasome-proteolytic pathway in oral epithelial cells, 2) determine the effects of ART on toll-like receptor (TLR) signaling pathways in oral epithelial cells, and 3) determine the effects of ART on oral epithelial cell differentiation. Specific biochemical and molecular methodologies are described that will allow us to systematically determine if ART adversely effects the proteasome function, TLR signaling and ability of epithelial cells to differentiate. These processes are key to maintaining oral mucosal health in patients who are infected with HIV and for understanding how opportunistic infections develop despite the presence of ART.