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

HIV 中一氧化氮的口腔微生物组和肠唾液循环。

• 批准号: 9103887
• 负责人: Carl D. Koch
• 金额: $ 7.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103887
• 关键词: 3-nitrotyrosine; AIDS/HIV problem; Activities of Daily Living; Affect; Antioxidants; Arginine; Atherosclerosis; Award; Bacteria; Bioavailable; Biology; Biometry; Blood Circulation; Blood Vessels; Brain natriuretic peptide; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catalytic Domain; Cerebrovascular Disorders; Chest; Chronic; Clinical; Clinical Research; Communities; DNA Sequence; Data; Deglutition; Development; Diet; Disease; Echocardiography; Enrollment; Enzymes; Exhibits; Fingerprint; Future; Generations; Glutathione; Goals; HIV; HIV Infections; Human; Hypoxia; IL6 gene; Immune; Individual; Inflammation; Injury; Interruption; Investigation; K-Series Research Career Programs; Laboratories; Lead; Life; Link; Lung; Lung diseases; Machine Learning; Maintenance; Maps; Master' s Degree; Measures; Mediating; Medicine; Mentors; Metabolism; Metagenomics; Methods; Mitochondria; Modeling; Morbidity - disease rate; Mucosal Immunity; Myocardial Infarction; N,N-dimethylarginine; N-terminal; NBL1 gene; NOS3 gene; National Research Service Awards; Nitrate Reductases; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Nitrite Reductase; Nitrites; Nitrogen; Oral; Oral cavity; Oxidative Stress; Oxygen; Participant; Pathogenesis; Pathway interactions; Phylogenetic Analysis; Physiological; Population; Production; Pulmonary Hypertension; Pulmonary artery structure; Pulmonology; Reperfusion Injury; Research; Research Design; Resources; Ribosomal DNA; Risk; Role; Salts; Sampling; Series; Serological; Signaling Molecule; Source; Stomach; Stress; Stretching; Supplementation; Taxon; Techniques; Testing; Time; Training; Translational Research; Universities; Vascular Diseases; Vascular Endothelium; Vasodilator Agents; antiretroviral therapy; base; blood pressure reduction; blood pressure regulation; cardiovascular health; cardiovascular risk factor; career; cohort; commensal microbes; experience; high risk; immune activation; improved; microbial; microbial community; microbiome; mortality; new therapeutic target; nitrogen metabolism; novel; novel diagnostics; novel therapeutic intervention; oral bacteria; oral commensal; oral microbiome; pressure; prevent; prospective; public health relevance; pyrosequencing; reconstruction; serological marker; skills; stem; symposium; targeted treatment

 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.

 描述（由申请人提供）：慢性 HIV 与肺部和心血管并发症的风险增加有关，尽管使用抗逆转录病毒治疗，但肺动脉高压等罕见血管并发症的发生率仍是 HIV 感染者的 25 倍以上。 HIV 中如此高的血管并发症发生率尚不清楚。一氧化氮 (NO) 是一种极其重要的信号分子，由血管内皮产生，充当血管舒张剂和心血管调节剂。最近，共生口腔细菌将硝酸盐还原为亚硝酸盐和一氧化氮，这与维持血管功能有关，因为硝酸盐被一系列细菌酶转化为亚硝酸盐，因此肠唾液一氧化氮途径是一氧化氮生成的重要组成部分。然后被吞咽并直接转化为 NO 或吸收到血液中，发挥类似 NO 的全身作用。肠唾液 NO 途径取决于存活的 NO 群体。然而，我们对所涉及的特定细菌群或对全身一氧化氮可用性以及血管损伤和疾病的贡献知之甚少。这项研究提出了一个新的假设，即艾滋病毒中出现的心脏加速和肺血管疾病部分是由于口腔微生物组的变化导致了口腔微生物组的破坏。为了检验这一假设，我们将使用独立于培养物的测序技术对特定口腔洗液样本中的 315 名 HIV+ 和 HIV- 参与者的口腔微生物组进行表征。将测量细菌硝酸盐还原酶，其结果与现有的血管损伤血清学标志物、超声心动图测试和血管损伤的放射学测量结果将直接为未来的临床提供信息。 参加一项前瞻性试验，检查实时硝酸盐代谢、全身一氧化氮分布和相关的生理效应，这些研究将为了解艾滋病毒相关血管疾病的新途径迈出第一步，并为靶向治疗的开发提供信息。将为肺医学研究员的候选人提供进一步接受肺血管医学培训以及发展艾滋病毒/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。通过实验室工作，导师 Morris 博士（HIV 相关肺部疾病和微生物组专家）和 Gladwin 博士（NO 和肺血管疾病专家）的资源和经验，以及临床/转化研究硕士学位。匹兹堡大学提供的广泛资源将支持候选人的成功发展。