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

短链脂肪酸：通过 HIV 感染者炎症小体失调促进口腔 HPV 的途径

• 批准号: 10532974
• 负责人: Josue Perez-Santiago
• 金额: $ 0.75万
• 依托单位: COMPREHENSIVE CANCER CENTER/ UNIV/PR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532974
• 关键词: Academic skills; Acquired Immunodeficiency Syndrome; Award; Butyrates; Clinical; Data; Data Analyses; Development; Doctor of Philosophy; Ensure; Enzyme-Linked Immunosorbent Assay; Genes; Genetic Transcription; Genotype; Goals; HIV; HIV Infections; Homeostasis; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immune; Immune System Diseases; Immunocompromised Host; Individual; Infection; Inflammasome; Inflammation; Innate Immune Response; Interdisciplinary Study; Interferons; Knowledge; Lead; Liquid Chromatography; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mentorship; Metagenomics; Natural History; Oral; Oral cavity; Oropharyngeal; Parents; Pathogenesis; Periodontal Diseases; Persons; Physicians; Play; Prevalence; Preventive; Proteins; Public Health; Puerto Rico; Research; Resources; Ribosomal DNA; Risk; Risk Factors; Role; Route; Saliva; Sampling; Statistical Data Interpretation; Tissues; Translational Research; Virus Diseases; Volatile Fatty Acids; Western Blotting; Writing; aged; cancer risk; carcinogenesis; career; design; dysbiosis; epidemiology study; experience; high risk; inflammatory marker; malignant oropharynx neoplasm; microbial; microbiome; microbiome research; novel; oral HPV; oral HPV infection; oral communication; oral microbial community; oral microbiome; pathogen; personalized therapeutic; programs; protein complex; research study; responsible research conduct; screening guidelines; skills; transmission process; tumorigenesis

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.

项目总结/文摘