Multi-Omics Predictors of Oral HPV Outcomes among PLWH

PLWH 口腔 HPV 结果的多组学预测

基本信息

批准号：
10557585
负责人：
Josue Perez-Santiago
金额：
$ 27.4万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557585
关键词：
21 year old Acquired Immunodeficiency Syndrome Affect Age Aging Behavioral Bioinformatics Biological Biological Aging Biological Assay Biological Process Biometry Blood Butyrates Cancer Biology Cancer health equity Cell Aging Characteristics Chronic Collection DNA Damage DNA Methylation Data Data Storage and Retrieval Development Diagnostic Disparity Early identification Enrollment Epidemiology Genome Genotype Goals HIV HIV Infections HPV oropharyngeal cancer Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Immune Immune response Immunologic Factors Immunosuppression Incidence Infection Inflammation Integration Host Factors Interdisciplinary Study Knowledge Longitudinal Studies Malignant Neoplasms Mentors Methylation Mucosal Immune Responses Mucosal Immunity Natural History Oral Oral Characters Oral cavity Oral health Outcome Oxidative Stress Pathogenicity Patient Recruitments Persons Predictive Factor Prevalence Prevention Preventive Public Health Puerto Rico Resources Ribosomal DNA Risk Risk Factors Risk Reduction Saliva Shapes Social Behavior Spectrophotometry Time Tissues Viral Virus Integration Visit Volatile Fatty Acids Woman Work antiretroviral therapy bead chip biobank cancer prevention cancer risk carcinogenesis community organizations dysbiosis experience genomic locus health disparity high risk population improved lifestyle factors machine learning classifier men methylation pattern methylome microbial microbiome multiple omics novel oral HPV oral HPV infection oral microbial community oral microbiome outreach prevent prognostic public education screening guidelines senescence social determinants social health determinants socioeconomic disadvantage socioeconomics tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Advances in antiretroviral therapy (ART) have not reduced the disproportional incidence and prevalence of oral human papilloma virus (HPV) and oropharyngeal cancers in people living with HIV (PLWH), suggesting ART alone may not fully restore mucosal immunity. This may be because HIV alters the oral microbiome, affecting mucosal immunity, and biological aging, such as changes in DNA methylation and immune senescence, can worsen HIV-associated immunosuppression. Reshaping the microbiome or reprogramming DNA methylation patterns may be a safe way to identify, prevent, or treat HPV persistence; however, understanding how these factors interact to promote cancer is a crucial gap in our existing knowledge. Our objective is to investigate these two biological processes (oral microbiome, biological aging), combined with socioeconomic and behavioral factors (sexual practices, lifestyle factors) to determine the impact of the natural history of HPV infection in PLWH, and to construct a machine learning classifier using these factors that can predict HPV infection and persistence. Our overarching hypothesis is that dysbiosis of the oral microbiome and older methylation aging are risk factors for HPV-related complications and can dampen the mucosal immune response in PLWH. Therefore, this proposed longitudinal study plans to collect saliva at two time points (baseline and after six months) from 150 virologically suppressed PLWH (men and women, ≥21 years old) from Puerto Rico CoNCRA, a community-based organization specialized in the prevention and treatment of HIV. PLWH who attend PR CoNCRA constitute a unique high-risk group where the prevalence of both HIV and oral HPV infection is higher, allowing our team of experts in HIV, HPV, epidemiology, cancer biology, oral health and bioinformatics to establish these relationships with high efficiency. The specific aims of this proposal are: (1) to determine how HPV incident infection and persistence affects the oral microbiome and oxidative stress in saliva in PLWH, (ii) to characterize the oral methylome of PLWH with and without HPV and assess the impact of methylation aging in the natural history of HPV infection, and (iii) to construct a diagnostic and prognostic classiﬁer based on biological data (microbiome and methylation) and socio-behavioral characteristics capable of discriminating HPV infection and persistence among PLWH. We will characterize the oral microbiota by 16S rDNA sequencing, HPV genotypes by PCR, DNA methylation by Illumina Infinium Methylation BeadChip arrays and oxidative stress by immuno spectrophotometry assays. Additionally, remaining saliva and voluntary blood collection will be used to create a biorepository for future research. This study leverages resources from the UPRCCC and CePCHE including (i) the UPRCCC Biobank for the biospecimen storage, (ii) the Biostatistics and Bioinformatics Core for assistance in the analyses and storage of the data generated, and (iii) the Outreach Core to help with participant recruitment and promotion of his project. This study will also provide data needed for R01 submission, and graduation of Dr. Josué Pérez-Santiago as a project leader of CePCHE.

项目概要/摘要抗逆转录病毒治疗（ART）的进步并没有降低口腔疾病的不成比例的发生率和患病率。人类乳头状瘤病毒 (HPV) 和艾滋病毒感染者 (PLWH) 的口咽癌，建议 ART 单独使用可能无法完全恢复粘膜免疫力，这可能是因为艾滋病毒改变了口腔微生物群，影响了口腔微生物群。粘膜免疫和生物衰老，例如DNA甲基化和免疫衰老的变化，可以延长 HIV 相关的免疫抑制重塑微生物组或重新编程 DNA 甲基化。模式可能是识别、预防或治疗 HPV 持续存在的安全方法，但要了解这些模式的作用；相互作用促进癌症的因素是我们现有知识中的一个重要空白，我们的目标是进行调查。这两个生物过程（口腔微生物组、生物衰老），与社会经济和行为相结合确定 HPV 感染自然史影响的因素（性行为、生活方式因素） PLWH，并使用这些因素构建机器学习分类器，可以预测 HPV 感染和我们的首要假设是口腔微生物组的菌群失调和较老的甲基化衰老。是 HPV 相关并发症的危险因素，可以抑制 PLWH 的粘膜免疫反应。因此，这项纵向研究计划在两个时间点（基线和六点后）收集唾液来自波多黎各 ConNCRA 的 150 名病毒学抑制的 PLWH（男性和女性，≥21 岁），专门从事预防和治疗参加 PR 的艾滋病毒感染者的社区组织。 CoNCRA 构成了一个独特的高危群体，其中 HIV 和口腔 HPV 感染的患病率较高，让我们的 HIV、HPV、流行病学、癌症生物学、口腔健康和生物信息学专家团队能够该提案的具体目标是：（1）确定如何高效地建立这些关系。 HPV 事件感染和持续性影响 PLWH 的口腔微生物组和唾液氧化应激，(ii) 描述感染和未感染 HPV 的 PLWH 的口腔甲基化组特征，并评估甲基化老化的影响 HPV 感染的自然史，以及 (iii) 基于生物学构建诊断和预后分类器能够区分 HPV 感染的数据（微生物组和甲基化）和社会行为特征我们将通过 16S rDNA 测序、HPV 来表征口腔微生物群。通过 PCR 进行基因型分析，通过 Illumina Infinium 甲基化 BeadChip 芯片进行 DNA 甲基化分析，通过氧化应激分析此外，剩余的唾液和自愿采血将用于进行免疫分光光度测定。为未来的研究创建一个生物样本库。本研究利用 UPRCCC 和 CePCHE 的资源。包括 (i) 用于生物样本存储的 UPRCCC 生物库，(ii) 用于存储生物样本的生物统计学和生物信息学核心协助分析和存储生成的数据，以及 (iii) 外展核心帮助参与者该研究还将提供 R01 提交所需的数据，以及 Josué Pérez-Santiago 博士作为 CePCHE 项目负责人毕业。