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.

美国牙周病学和欧洲牙周病学会最近采用了 新的术语“ C级牙周炎”，以识别具有高风险进展风险的个体。 该疾病的局部形式，现在称为3-4级C，摩尔引起的牙周炎（C/MIP）， 表现出非常明确的临床表现。尽管不如其他牙周炎常见，但C/MIP具有 严重的公共卫生影响，因为它影响了社会经济学低的系统健康的年轻人 地位，通常负担不起其昂贵且复杂的治疗的状态，因为经常会丢失受影响的牙齿 它的快速发展和延迟的诊断。这导致早期功能和美学问题和终身性 功能和美学康复的困难。由于其在家庭中的共同汇总，几项研究 已经搜索了与C级疾病的遗传关联，但不在大量C/MIP中。那，遗传 尚未确定C/MIP的贡献。团队为此提案组成了基础 - 在过去的3年中，该领域的破坏工作，包括鉴定候选遗传易感性 变体，高炎症反应以及与AA和AA JP2克隆的牢固关联。但是，不同 种群具有不同的遗传易感性，环境暴露和微生物定植，这些遗传倾向 进一步复杂化了这种疾病的真实病因和发病机理。那是迫切需要的 检查来自不同世界地区的大量C/MIP家族的大量明确定义的队列 全面确定该疾病的遗传，宿主反应和微生物决定剂。目标 该建议是表征早期发作的遗传，宿主和微生物因子 全世界种群中牙周炎的形式。我们建议通过收集大量C/MIP家族来做到这一点 在4个不同的大洲至1）通过WES识别C/MIP家族中的遗传敏感性变异； 2）确定 通过转录组和网络分析和炎症性与C/MIP 2相关的炎症网络 这些受影响家庭的口腔环境中的调解人概况； 3）确定常见的微生物组轮廓 通过宏基因组分析和来自世界不同地区的C/MIP家族中的独特AA菌株相关 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 可能在地球的不同区域有所不同，2-A特异性转录组与促炎的途径有关 C/MIP以及3基类型和表观上不同的AA菌株在全球区域之间会有所不同 将与具有不同功能和病毒潜力的微生物组群落相关。 拟议工作的影响是开发一系列互动网络的集成系列和 功能分析，这将导致易感性，分子和微生物表型的表征 世界各地不同人群的C/MIP，这将为早期疾病诊断和 开发这些高度易感家庭的有针对性和个性化疗法。