Proof of Concept: Scardovia wiggsiae is Cariogenic in vivo

描述（由申请人提供）：虽然已经证明双歧杆菌科物种与龋齿密切相关，但有关这些物种致龋性的信息有限。这项研究项目的长期目标是减少并最终帮助预防儿童早期龋齿（ECC）。本R21申请的目的是证明/反驳与严重ecc显著相关的Scardovia wiggsiae在体内具有龋齿性的概念。核心假设是，wiggsiae会在体内诱导牙齿脱矿并产生龋齿，可能单独作用，也可能与变形链球菌协同作用。这一提议的基本原理是，体内蛀牙潜力的证据将证明深入研究细菌与人类牙齿健康的相关性，如果是这样，它的蛀牙机制。本应用程序的中心假设和目标的实现将通过以下两个具体目标进行测试。目的1：研究维氏卡杜氏菌的体内致病性。目前的假设是，斯卡多维亚会在动物模型系统中定居并诱导牙齿脱矿。不同浓度的微生物将被用来接种给喂食致龋饮食的斯普拉格·道利大鼠。将对动物进行威氏s.g gsiae的定植和组织入侵测试，并对龋齿进行评分。目的2：研究变形链球菌在体内的致病性。检测到威格氏葡萄球菌和变形葡萄球菌定殖的儿童与严重ecc之间存在显著关联。目前的假设是，wiggsiae和变形链球菌的组合比单独的任何一种都能在牙齿上定居并诱导更多的牙齿脱矿。在第2项研究中，将在第1项研究中使用的同一动物模型中，比较wiggsiae和变形葡萄球菌单独感染诱导龋齿的能力与wiggsiae和变形葡萄球菌合并感染的能力。测试物种定植和组织入侵，并分析龋齿。Aim 1的预期结果将是证明一种与严重ecc显著相关的新命名物种的致病性，Aim 2的预期结果将是证明wiggsiae与S. mutans的联合感染增强了致病性。该研究结果将对该领域产生重要的积极影响，因为它表明需要进一步研究该物种与不同龋风险人群的关系，并确定其致龋机制，从而为未来改进儿童早期龋的微生物诊断、风险评估和治疗奠定基础。这项研究具有重要意义，因为它有望在假设威氏s.g gsiae是人类龋齿病原体的基础上，在R01水平上进行后续的明确研究。虽然这一建议源于与严重ecc相关的物种，但研究结果将直接应用于成人龋齿的研究，包括快速进展的冠状和牙根病变。

DESCRIPTION (provided by applicant): While it has been demonstrated that Bifidobacteriaceae species are strongly associated with dental caries, there is limited information about cariogenicity of these species. The long-term goal of this research project is to reduce and ultimately help prevent early childhood caries (ECC). The objective of this R21 application is to prove/disprove the concept that Scardovia wiggsiae, which was detected as significantly associated with severe-ECC, is cariogenic in vivo. The central hypothesis is that S. wiggsiae will induce tooth demineralization and produce caries in vivo, acting either acting alone or in synergy with Streptococcus mutans. The rationale for this proposal is that proof of cariogenic potential in vivo would justify in- depth studies of the bacterium's relevance to human dental health, and if so, its cariogenic mechanisms. The central hypothesis and accomplishment of the objective of this application will be tested with the following two specific aims. Aim 1: Cariogenicity of Scardovia wiggsiae in vivo. The working hypothesis is that Scardovia wiggsiae will colonize and induce tooth demineralization in an animal model system. Differing concentrations of the organism will be used to inoculate Sprague Dawley rats fed a cariogenic diet. Animals will be tested for colonization and tissue invasion by S. wiggsiae, and scored for caries. Aim 2: Cariogenicity of Scardovia wiggsiae with S. mutans in vivo. Significant associations between children colonized by both S. wiggsiae and S. mutans and severe-ECC were detected. The working hypothesis is that a combination of S. wiggsiae and S. mutans will colonize and induce more tooth demineralization than either species alone. In Aim 2, the ability for separate infections by S. wiggsiae and S. mutans to induce caries will be compared with a combined S. wiggsiae and S. mutans infection in the same animal model used in Aim 1. Test species colonization and tissue invasion, and dental caries will be assayed. The expected outcomes in Aim 1 will be the demonstration of cariogenicity of a newly named species significantly associated with severe-ECC, and in Aim 2 demonstration of enhanced cariogenicity by the combined infection of S. wiggsiae with S. mutans. The expected confirmation that S. wiggsiae is cario- genic in vivo would have an important positive impact on the field because it would indicate the need for further investigation into the association of the species with diverse populations at risk for caries and determining mechanism(s) of cariogenicity on which to base future improved microbial diagnosis, risk assessment and treatment for early childhood caries. The research proposed is significant because it is expected to enable subsequent definitive studies at the R01 level based on the hypothesis that S. wiggsiae is a caries pathogen in humans. While this proposal stems from species association with severe-ECC, the findings will have direct application for studies of caries in adults including rapidly progressing coronal and root lesions. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will prove or disprove the concept that Scardovia wiggsiae is cariogenic. If this species proves to be cariogenic, it would be of public health relevance to test it as a risk indicator for dental caries which would particularly benefit populations with oral health disparities that experience rampant/severe-ECC. The proposed research is relevant to the part of NIH's mission that is described in the priorities of the strategic plan of NIDCR (2009-2013) by integrating a molecular and clinical (in vivo disease model) approach to prove or disprove a diagnostic biomarker for caries risk (Objective I-1), and examining factors that could contribute to oral health inequality (Objective IV-1).