The microbiome associated with oral Leukoplakia: A multi-omics mechanistic study

与口腔白斑相关的微生物组：一项多组学机制研究

• 批准号: 10870268
• 负责人: Nezar Al-Hebshi
• 金额: $ 41.43万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10870268
• 关键词: Accounting; Address; Algorithms; American; Animals; Artificial Intelligence; Automobile Driving; Binding Proteins; Bioinformatics; Biological Markers; Canada; Candida; Candida albicans; Case/Control Studies; Cell Proliferation; Cessation of life; Coculture Techniques; Complement; Coupled; DNA; Data; Detection; Development; Diagnostic; Disease; Dysplasia; Early Intervention; Enrollment; Epithelial Cells; Epithelium; Event; Foundations; Fusobacterium; Fusobacterium nucleatum; Future; Gene Expression; Genes; Genotype; Goals; Health; Healthcare Systems; Human; In Vitro; International; Intervention; Intraepithelial Neoplasia; Invaded; Knowledge; Lesion; Longitudinal Studies; Malignant - descriptor; Malignant Neoplasms; Marker Discovery; Matrix Metalloproteinases; Mediating; Mesenchymal; Metagenomics; Metals; Oncogenic; Oral; Oral Leukoplakia; Oral Stage; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Phase; Phenotype; Pilot Projects; Population; Prevention; Process; Production; Prognosis; Proliferating; Property; Research; Resolution; Resources; Role; Saliva; Sampling; Severities; Shotguns; Swab; Transforming Growth Factor beta; Up-Regulation; analysis pipeline; bioinformatics pipeline; carcinogenesis; carcinogenicity; cohort; comparison group; cost; cytokine; data integration; diagnostic biomarker; dysbiosis; early detection biomarkers; epithelial to mesenchymal transition; experimental study; high risk; host-associated microbial communities; host-microbe interactions; improved; insight; interest; knock-down; malignant mouth neoplasm; metagenomic sequencing; metatranscriptome; microbial; microbial community; microbial composition; microbial signature; microbiome; microbiome composition; microorganism; mouth squamous cell carcinoma; multiple omics; noninvasive diagnosis; novel; novel diagnostics; oral carcinogenesis; oral cavity epithelium; oral dysplasia; oral microbiome; premalignant; prognostic; prospective; recruit; response; saliva sample; secondary analysis; transcriptome; tumor microenvironment; Accounting; Address; Algorithms; American; Animals; Artificial Intelligence; Automobile Driving; Binding Proteins; Bioinformatics; Biological Markers; Canada; Candida; Candida albicans; Case/Control Studies; Cell Proliferation; Cessation of life; Coculture Techniques; Complement; Coupled; DNA; Data; Detection; Development; Diagnostic; Disease; Dysplasia; Early Intervention; Enrollment; Epithelial Cells; Epithelium; Event; Foundations; Fusobacterium; Fusobacterium nucleatum; Future; Gene Expression; Genes; Genotype; Goals; Health; Healthcare Systems; Human; In Vitro; International; Intervention; Intraepithelial Neoplasia; Invaded; Knowledge; Lesion; Longitudinal Studies; Malignant - descriptor; Malignant Neoplasms; Marker Discovery; Matrix Metalloproteinases; Mediating; Mesenchymal; Metagenomics; Metals; Oncogenic; Oral; Oral Leukoplakia; Oral Stage; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Phase; Phenotype; Pilot Projects; Population; Prevention; Process; Production; Prognosis; Proliferating; Property; Research; Resolution; Resources; Role; Saliva; Sampling; Severities; Shotguns; Swab; Transforming Growth Factor beta; Up-Regulation; analysis pipeline; bioinformatics pipeline; carcinogenesis; carcinogenicity; cohort; comparison group; cost; cytokine; data integration; diagnostic biomarker; dysbiosis; early detection biomarkers; epithelial to mesenchymal transition; experimental study; high risk; host-associated microbial communities; host-microbe interactions; improved; insight; interest; knock-down; malignant mouth neoplasm; metagenomic sequencing; metatranscriptome; microbial; microbial community; microbial composition; microbial signature; microbiome; microbiome composition; microorganism; mouth squamous cell carcinoma; multiple omics; noninvasive diagnosis; novel; novel diagnostics; oral carcinogenesis; oral cavity epithelium; oral dysplasia; oral microbiome; premalignant; prognostic; prospective; recruit; response; saliva sample; secondary analysis; transcriptome; tumor microenvironment

Project Summary There is increasing interest in the role of the microbiome in the development and/or progression of various cancers including oral squamous cell carcinoma (OSCC). Research has shown that OSCC is associated with a distinct microbiome. However, OSCC in itself represents a late stage in a disease process in which the observed microbial changes are as likely to be passenger or, at best, late driving events. To better understand the role of the microbiome in OSCC and identify microbial biomarkers for early detection and prevention, it is crucial to assess the microbiome in early stages of the disease, e.g. oral potentially malignant disorders (OPMDs). Oral leukoplakia (OL; the focus of this study) is the most common OPMD. Little is known about the microbiome associated with OPMDs, its role in their progression, or its potential as non-invasive diagnostic biomarker to complement oral epithelial dysplasia grading, currently the best available indicator. Our long-term goal is to identify diagnostic/prognostic microbial biomarkers of OPMDs and determine the effect of the microbiome on oral carcinogenesis by conducting a large-scale, international consortium study in two phases: a case-control study (this application) to comprehensively study the dysbiotic microbiome associated with OL/dysplasia in a North American population; followed by a longitudinal study (future application) that will involve following up the same and additional cohorts of OPMDs to identify/validate microbiome biomarkers of malignant transformation (MT). Our hypothesis is that shifts in microbiome composition and function associated with OL represent early driver events that correlate with the severity of dysplasia and contribute to the progression of oral cancer. In addition, we also hypothesize that oncogenic strains of oral microorganisms could be driving these disorders. To address these hypotheses, we propose 3 specific aims: 1) Characterize the composition of the multi-kingdom microbiome associated with OL and the different grades of dysplasia; 2) Define both microbial and host transcriptomes in OL and potential interactions between these two segments of the metatranscriptome. 3) Assess in vitro the oncogenic properties of bacterial and fungal strains isolated from OL. The study will be conducted by a team of international experts and will enroll 210 OL patients, 105 OSCC patients, and 420 healthy control subjects (735 subjects in total) to be recruited in two study centers. One-thousand and five hundred saliva and swab samples will be analyzed using shotgun metagenomic and metatranscriptome analysis. Furthermore, 36 bacterial/fungal strains previous isolated from OL patients with different grades of dysplasia will be screened for their effect on proliferation, invasion, epithelial-mesenchymal transition and cytokine and matrix metalloproteinases production by normal and dysplastic epithelial cells in vitro. The study will establish the role of the microbiome in the early stages of oral carcinogenesis, and identify microbial biomarkers of OL and dysplasia, which in a subsequent study can be validated as biomarkers of MT.

项目摘要 对微生物组在各种发展和/或发展中的作用的兴趣越来越大 包括口服鳞状细胞癌（OSCC）在内的癌症。研究表明，OSCC与 独特的微生物组。但是，OSCC本身代表了观察到的疾病过程中的后期 微生物的变化可能是乘客，或者充其量是较晚的驾驶活动。更好地了解 OSCC中的微生物组并识别微生物生物标志物以进行早期检测和预防，这对 评估疾病早期的微生物组，例如口腔潜在的恶性疾病（OPMD）。口服 白细胞（本研究的重点）是最常见的OPMD。关于微生物组知之甚少 与OPMD相关，其在其进展中的作用或作为非侵入性诊断生物标志物的潜力 补充口腔上皮发育不良分级，目前是最好的指标。我们的长期目标是 识别OPMD的诊断/预后微生物生物标志物，并确定微生物组对 口服致癌作用是通过两个阶段进行大规模的国际财团研究：一个病例对照 研究（该应用）是为了全面研究与OL/异常增生症相关的不植物微生物组 北美人口；然后进行纵向研究（未来应用），该研究将涉及跟进 相同和其他opmds的同类群体，以识别/验证恶性转化的微生物组生物标志物 （公吨）。我们的假设是，与OL相关的微生物组组成和功能的转移表示早期 与发育不全严重程度相关并导致口腔癌进展的驾驶员事件。在 此外，我们还假设口服微生物的致癌菌株可能会驱动这些疾病。 为了解决这些假设，我们提出了3个具体目的：1）表征多国的组成 与OL相关的微生物组和不同等级的发育不全； 2）定义微生物和宿主 OL中的转录组和元共转录组的这两个段之间的潜在相互作用。 3） 在体外评估细菌和真菌菌株从OL分离的致癌特性。该研究将是 由一个国际专家团队进行，将注册210名OL患者，105名OSCC患者和420名健康 在两个研究中心将招募对照受试者（总共735名受试者）。一千和五百个唾液 将使用shot弹枪元基因组和元文字分析分析拭子样品。此外， 36个细菌/真菌菌株先前从不同等级发育不良的OL患者中分离出来 因为它们对增殖，侵袭，上皮 - 间质转变以及细胞因子和基质的影响 在体外由正常和发育不良上皮细胞产生的金属蛋白酶。该研究将确定角色 在口服癌变的早期阶段的微生物组，并确定OL和OL的微生物生物标志物 在随后的研究中可以证实发育不良，可以被验证为MT的生物标志物。