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，是全世界死亡的主要原因。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采用大大降低了发病率和死亡率。然而，ART必须终生服用，并且几种长期效应（例如血脂异常、线粒体功能障碍、外分泌病理学）最近才被认识到。缺乏关于ART对口腔粘膜不良影响的研究。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。这方面的知识是了解长期影响ART的至关重要的粘膜和上皮细胞在控制口腔机会性感染的HIV感染者的一个必要条件。拟议研究的一般假设是选择ART药物失调口腔上皮细胞生物学，影响正常的蛋白酶体途径，上皮细胞稳态和先天免疫参数，导致口腔粘膜和上皮细胞对微生物病原体的反应能力的有害变化。我们的具体目标是1）检查ART对口腔上皮细胞中蛋白酶体蛋白水解途径的影响，2）确定ART对口腔上皮细胞中Toll样受体（TLR）信号通路的影响，以及3）确定ART对口腔上皮细胞分化的影响。 具体的生物化学和分子方法进行了描述，这将使我们能够系统地确定，如果艺术的蛋白酶体功能，TLR信号和上皮细胞分化的能力产生不利影响。这些过程是维持HIV感染患者口腔粘膜健康的关键，也是了解尽管存在ART，机会性感染如何发展的关键。

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.