The oral microbiome and enterosalivary circulation of nitric oxide in HIV.

 描述（由申请人提供）：慢性HIV与肺和心血管并发症的风险增加有关。尽管使用了抗逆转录病毒疗法，但即使是罕见的血管并发症，如肺动脉高压的发生率也是艾滋病毒感染者的25倍以上。艾滋病患者血管并发症发生率如此之高的原因尚不清楚。一氧化氮（NO）是一种非常重要的信号分子，由血管内皮细胞产生，并作为血管扩张剂和心血管健康的调节剂。最近研究表明，口腔细菌将硝酸盐还原为亚硝酸盐和一氧化氮与维持血管功能有关。肠唾液NO途径是一氧化氮产生的重要组成部分，因为硝酸盐在口腔中被一系列细菌酶转化为亚硝酸盐，然后被吞咽并直接转化为NO或吸收到血流中，在那里发挥全身NO样作用。肠唾液NO途径依赖于口腔细菌的存活群体，并有助于调节血压和减轻血管损伤。然而，关于涉及的特定细菌群体或对全身NO可用性和血管损伤和疾病的贡献知之甚少。我们的初步研究表明，HIV+个体的口腔细菌（口腔微生物组）与HIV-个体不同，涉及关键的硝酸盐还原途径。这项研究提出了一个新的假设，即在HIV中观察到的加速心血管和肺血管疾病部分是由于口腔微生物组的变化，这些变化有利于破坏肠唾液NO通路，降低NO可用性和慢性血管损伤。为了验证这一假设，将使用库存口腔洗液样本中的培养物独立测序技术对315名HIV+和HIV-受试者的已建立队列的口腔微生物组进行表征。将测量特定细菌硝酸盐还原酶的表达，并将结果与血管损伤的可用血清学标志物、超声心动图检测和血管损伤的放射学测量相关联。结果将直接告知未来的临床 招募一项前瞻性试验，检查实时硝酸盐代谢、全身NO分布和相关生理效应。这些研究将为理解HIV相关血管疾病的新途径提供第一步，并为靶向治疗的发展提供信息。此外，该NRSA奖将为候选人，肺医学研究员，提供进一步培训肺血管医学和发展艾滋病毒/艾滋病和微生物组研究技能的机会。候选人将通过实验室工作，会议和临床/转化研究硕士学位获得基础和高级实验室技术，生物统计学和临床研究设计方面的广泛培训。莫里斯博士，在艾滋病毒相关的肺部疾病和微生物组的专家，和Gladwin博士，在NO和肺血管疾病的专家，结合在匹兹堡大学可用的资源的广泛阵列的资源，将支持候选人的成功发展。

 DESCRIPTION (provided by applicant): Chronic HIV is associated with increased risk of pulmonary and cardiovascular complications. Despite use of antiretroviral therapy, rates of even rare vascular complications such as pulmonary hypertension occur upwards of 25 times that in HIV- individuals. The cause for such a high rate of vascular complications in HIV is unknown. Nitric oxide (NO) is a critically important signaling molecule that is produced by the vascular endothelium and acts as a vasodilator and regulator of cardiovascular health. Reduction of nitrate to nitrite and nitric oxide by commensal oral bacteria has recently been implicated in the maintenance of vascular function. The enterosalivary NO pathway is an important component of nitric oxide generation as nitrate is converted to nitrite by a series of bacterial enzymes in the mouth, which is then swallowed and either directly converted to NO or absorbed into the bloodstream where it exerts systemic NO-like effects. The enterosalivary NO pathway depends on viable populations of oral bacteria and helps regulate blood pressure and mitigate vascular injury. However, little is known about the specific bacterial populations involved or the contribution to systemic NO availability and vascular injury and disease. Our preliminary studies suggest that HIV+ individuals have a different profile of oral commensal bacteria (oral microbiome) than HIV- individuals that involves key nitrate reduction pathways. This study proposes the novel hypothesis that the accelerated cardio- and pulmonary vascular disease seen in HIV is due in part to changes in the oral microbiome that favor a disruption of the enterosalivary NO pathway, reduced NO availability, and chronic vascular injury. To test this hypothesis, the oral microbiome of an established cohort of 315 HIV+ and HIV- participants will be characterized using culture-independent sequencing techniques in banked oral wash samples. Expression of specific bacterial nitrate-reducing enzymes will be measured, and results correlated with available serological markers of vascular damage, echocardiographic testing, and radiographic measures of vascular injury. Results will directly inform future clinical enrollment of a prospective trial examining real-time nitrate metabolism, systemic NO distribution, and associated physiological effects. These investigations will offer the first stepsin understanding a novel pathway of HIV-associated vascular disease and inform development of targeted therapies. Additionally, this NRSA award will provide the candidate, a pulmonary medicine fellow, the opportunity for further training in pulmonary vascular medicine and for developing skills in HIV/AIDS and microbiome research. The candidate will acquire extensive training in basic and advanced laboratory techniques, biostatistics, and clinical study design through labwork, conferences, and a master's degree in clinical/translational research. The resources and experience of mentors Dr. Morris, an expert in HIV-related lung disease and the microbiome, and Dr. Gladwin, an expert in NO and pulmonary vascular disease, combined with the expansive array of resources available at the University of Pittsburgh, will support the candidate's successful development.