Short Chain Fatty Acids: Route for Facilitation of Oral HPV via Inflammasome Dysregulation in People Living with HIV

项目摘要/摘要 口腔微生物区系和炎症体蛋白复合体是维持免疫的重要因素 动态平衡，这是由艾滋病毒感染改变，并已观察到在发病机制中 口咽癌。口腔中的短链脂肪酸(SCFA)，如丁酸盐，会加剧 牙周组织损伤，可作为肿瘤代谢物，导致HPV相关疾病的发展 口腔和咽癌的发生。此外，丁酸还被发现可以调节转录 免疫相关基因。特别是，它上调局部炎症，同时下调血管内皮生长因子的表达 干扰素相关基因和上调炎症体相关标记物，是天然免疫所必需的 对病毒感染的反应。因此，丁酸盐可能通过以下途径在免疫功能障碍中发挥重要作用 调节炎症小体和促进口腔HPV感染，增加患者的癌症风险 艾滋病毒(PLWH)。因此，我们的总体目标是量化无HPV感染的PLWH患者的口腔SCFA。 根据中心假设，口腔HPV感染的PLWH将有更高水平的丁酸盐，这将是 与牙周病、口腔微生物群失调、更多炎症和更多 炎症性失调症。这项补充计划使用50个病毒学抑制的PLWH样本 (25例HPV阳性和25例HPV-)，来自父母研究的21岁和49岁的≥。这项建议的具体目的 是(I)量化PLWH唾液中微生物SCFA的水平，并评估它们与感染和 HPV基因分型(高危与低危)和(Ii)确定SCFA水平与 牙周病、口腔微生物群失调、炎症体失调和炎症水平 记号笔。SCFA的测定采用高效液相色谱-质谱法。我们将利用 Hpv基因分型(Pcr)、口腔微生物组数据(16S rdna图谱)、炎症体蛋白水平(Western印迹) 和炎性标志物(多重酶联免疫吸附试验)来自父母的研究。这一奖项将直接支持亚布迪尔先生 Ramos-Valerio在微生物组研究和数据分析方面取得专业知识，包括大规模 元基因组学数据以及统计分析和流行病学研究的重点是艾滋病毒、HPV和癌症。他 还将参加课程并专注于扩大他在设计方面的知识和经验， 实施并完成临床/转化性研究研究。最后，他将进一步发展学术 确保他成功、独立的研究生涯的技能，包括负责任的研究行为， 科学写作、口头交流技能、勇气和协作的跨学科研究。这 补习生将为他提供资源，以实现他被医学/博士项目录取的目标 并最终成为一名专门研究病原体驱动的癌症的独立研究医生。

PROJECT SUMMARY/ABSTRACT The oral microbiota and inflammasome protein complex are essential factors for maintaining immune homeostasis, which are altered by an HIV infection and have been observed in the pathogenesis of oropharyngeal cancer. Short chain fatty acids (SCFA) in the oral cavity, such as butyrate, exacerbates periodontal tissue damage, which can act as an oncometabolite and lead to the development of HPV-related oral and pharyngeal carcinogenesis. Furthermore, butyrate has been found to regulate the transcription of immune-related genes. Particularly, it upregulates local inflammation while downregulates the expression of interferon-related genes and upregulates inflammasome-related markers, necessary for the innate immune response to a viral infection. Therefore, butyrate could play an essential role on immune dysfunction by dysregulating the inflammasome and facilitating oral HPV infection, increasing cancer risk in people living with HIV (PLWH). Therefore, our overall objective is to quantify oral SCFA in PLWH with an without HPV infection with the central hypothesis that PLWH with oral HPV infection will have higher levels of butyrate, which will be associated with periodontal disease, dysbiosis of the oral microbiome, more inflammation and more inflammasome dysregulation. This supplement plans to use samples from 50 virologically suppressed PLWH (25 HPV+ and 25 HPV-), aged ≥21 and<49 years old from the parent study. The specific aims of this proposal is (i) to quantify the levels of microbial SCFA in saliva of PLWH and assess their relationship with infection and HPV genotypes (high-risk vs. low-risk) and (ii) To determine the association between the levels of SCFA with periodontal disease, oral microbiome dysbiosis, inflammasome dysregulation and levels of inflammation markers. SCFA will be measured by liquid chromatography followed by mass spectrometry. We will leverage HPV genotyping (PCR), oral microbiome data (16s rDNA profiling), inflammasome proteins levels (western blot) and inflammatory markers (multiplex ELISA) from the parent study. This award will directly support Mr. Yabdiel Ramos-Valerio in achieving expertise in microbiome research and data analysis, including large-scale metagenomics data and statistical analysis and epidemiological research focused on HIV, HPV, and cancer. He will also take courses and focused mentorship on expanding his knowledge and experience in designing, implementing, and completing a clinical/translational research study. Finally, he will further develop the academic skills that will ensure his successful, independent research career, including responsible conduct of research, scientific writing, oral communication skills, grantsmanship, and collaborative interdisciplinary research. This supplement will provide him with resources toward achieving his goal of being accepted in MD/PhD programs and eventually become an independent research physician specializing in pathogen-driven cancers.