Susceptibility Patterns for Grade C Periodontitis in Young Individuals

年轻人 C 级牙周炎的易感性模式

• 批准号: 10708858
• 负责人: Luciana Macchion Shaddox
• 金额: $ 112.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708858
• 关键词: Academy; Actinobacillus actinomycetemcomitans; Adopted; Affect; African ancestry; Age; American; Bacteria; Characteristics; Clinical; Communities; Complex; DNA; DNA sequencing; Development; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disease; Disease Progression; Economics; Elderly; Environment; Environmental Exposure; Epithelial Cells; Esthetics; Etiology; European; Exhibits; Family; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Geographic Locations; Gingival Crevicular Fluid; Goals; Immune response; Incisor; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Link; Metagenomics; Molecular; Multicenter Studies; Names; Oral; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Periodontitis; Phenotype; Population; Predisposition; Property; Public Health; Rehabilitation therapy; Saliva; Sampling; Series; Shotguns; Siblings; Site; Susceptibility Gene; Taxonomy; Terminology; Testing; Tooth structure; Variant; Virulence; Virulent; Work; candidate identification; case control; cohort; data integration; disease diagnosis; early onset; exome sequencing; gene interaction; genetic association; genetic variant; genome-wide analysis; high risk; individualized medicine; metagenome; microbial; microbial colonization; microbial community; microbiome; neutrophil; oral cavity epithelium; oral microbiome; peripheral blood; social; targeted treatment; transcriptome; transcriptome sequencing

The American Academy of Periodontology and European Federation of Periodontology have recently adopted the new terminology, “Grade C Periodontitis,” to identify individuals with a high risk for disease progression. The localized form of this disease, now termed Stage 3-4 Grade C, molar-incisor pattern periodontitis (C/MIP), exhibits a very well-defined clinical presentation. Although less common than other periodontitis, C/MIP has a significant public health impact, as it affects systemically healthy, young individuals, of low social economic status, who usually cannot afford its expensive and complex treatment, as their affected teeth are often lost due to its rapid progression and delayed diagnosis. This leads to early function and aesthetics issues and life-long difficulties for functional and aesthetic rehabilitation. Due its common aggregation in families, several studies have searched for genetic associations with grade C disease, but not in large cohorts of C/MIP. Thus, genetic contributions for C/MIP are not yet identified. The team put together for this proposal have conducted ground- breaking work in this field over the last 3 decades, including the identification of candidate genetic susceptibility variants, hyper-inflammatory response, and strong association with Aa and Aa JP2 clone. However, different populations have different genetic predispositions, environmental exposures, and microbial colonization, which further complicates unveiling the true etiology and pathogenesis of this disease. Thus, there is a critical need to examine a large well-defined cohort of C/MIP families from different world regions to systematically and comprehensively determine the genetic, host response, and microbial determinants of this disease. The goal of this proposal is to characterize the genetic, host, and microbial factors of the early onset, well-defined, localized form of periodontitis in populations worldwide. We propose to do this by gathering large cohort of C/MIP families in 4 different continents to 1)identify genetic susceptibility variants within C/MIP families via WES; 2)Identify the inflammatory networks associated with C/MIP 2, via transcriptome and network analysis and inflammatory mediator profile in the oral environment of these affected families; and 3) Determine common microbiome profiles via metagenomic analysis and unique Aa strains in C/MIP families from different regions of the world associated with this disease. Our hypotheses are that 1-C/MIP will be associated with identifiable genetic variants, which may vary in different regions of the globe, 2-a specific transcriptome is linked to pro-inflammatory pathways in C/MIP, and 3-genotypically and phenotypically different strains of Aa will differ among regions of the globe and will correlate with microbiome communities of distinct functionality and virulence potential. The impact of the proposed work is the development of an integrative series of interaction network and functional analyses, which will lead to the characterization of susceptibility, molecular, and microbial phenotypes of C/MIP in different populations around the world, which will provide criteria for early disease diagnosis and development of targeted and individualized therapies for these highly susceptible families.

美国牙周病学会和欧洲牙周病学会最近通过了 新术语“C级牙周炎”用于识别疾病进展高风险的个体。这 这种疾病的局部形式，现在称为 3-4 级 C 级，磨牙-切牙型牙周炎 (C/MIP)， 表现出非常明确的临床表现。虽然 C/MIP 比其他牙周炎不太常见，但它具有 重大公共卫生影响，因为它影响社会经济水平较低的系统健康的年轻人 他们通常无力承担昂贵且复杂的治疗，因为他们受影响的牙齿经常因脱落而脱落 其快速进展和延迟诊断。这导致了早期的功能和美观问题以及终生的问题。 功能和美观康复困难。由于其在家庭中普遍聚集，一些研究 已经搜索了与 C 级疾病的遗传关联，但没有在大型 C/MIP 队列中进行搜索。因此，遗传 对 C/MIP 的贡献尚未确定。为此提案组建的团队进行了基础研究 过去三十年该领域的突破性工作，包括识别候选遗传易感性 变异、高炎症反应以及与 Aa 和 Aa JP2 克隆的强相关性。然而，不同 不同人群有不同的遗传倾向、环境暴露和微生物定植， 进一步复杂化揭示这种疾病的真正病因和发病机制。因此，迫切需要 研究来自世界不同地区的一大群明确定义的 C/MIP 家庭，以系统地和 综合确定该疾病的遗传、宿主反应和微生物决定因素。目标是 该提案旨在描述早期发病、明确、局部的遗传、宿主和微生物因素。 全世界人群中牙周炎的一种形式。我们建议通过聚集大量 C/MIP 家庭来做到这一点 在 4 个不同的大陆，1) 通过 WES 识别 C/MIP 家族内的遗传易感性变异； 2）确定 与 C/MIP 2 相关的炎症网络，通过转录组和网络分析以及炎症 这些受影响家庭口腔环境中的中介者概况； 3) 确定常见的微生物组概况 通过宏基因组分析和来自世界不同地区的 C/MIP 家族中独特的 Aa 菌株相关 患有这种疾病。我们的假设是 1-C/MIP 将与可识别的遗传变异相关，这 全球不同地区可能有所不同，2-特定转录组与促炎症途径相关 C/MIP 以及 3-基因型和表型不同的 Aa 菌株在全球各地区之间会有所不同 将与具有不同功能和毒力潜力的微生物群落相关联。 所提出的工作的影响是开发一系列综合的交互网络和 功能分析，这将导致敏感性、分子和微生物表型的表征 世界各地不同人群中 C/MIP 的研究，这将为早期疾病诊断和治疗提供标准 为这些高度易感的家庭开发有针对性的个体化疗法。