Functional role of Serum Amyloid A in periapical inflammation

描述(申请人提供)：虽然牙髓感染会导致根尖周围损害，但这种疾病的病程也会受到宿主因素的影响。例如，长期糖尿病患者的牙齿比短期糖尿病患者的根尖周病变更大， 健康对照组。到目前为止，细菌病原体/病原体相关分子模式(PAMPs)与宿主免疫系统之间的关系已经被广泛研究。然而，宿主衍生的危险相关分子模式(DAMP)由受损细胞释放，在根尖周病变中的参与尚不清楚。在我们的初步研究中，SAA3(血清淀粉样蛋白A3)是一种潮湿的基因，在啮齿类动物的根尖周病变中表达最高，SAA3蛋白在小鼠的根尖周病变中强烈表达。在小鼠饮食诱导肥胖模型(DIO)中，与对照组相比，动物发展为糖尿病前期和脂肪变性(脂肪肝)，全身SAA水平显著升高，表明SAA与肥胖诱导的全身炎症有关。此外，感染DIO的小鼠表现出血清SAA升高，与对照组相比，根尖周围病变更大，这表明SAA和根尖周围病变的严重程度之间存在病理联系。这一建议的中心假设是，SAA是对牙科感染的反应，它加剧了牙槽骨的破坏，并进一步促进了肥胖症/2型糖尿病的全身炎症及其后遗症。我们认为SAA是根尖周病变中的主要湿润物质，也是牙槽骨炎症的关键增强剂。因此，SAA是调节口腔感染和炎症的创新靶点。我们将在以下三个具体目标中探讨SAA在根尖周病变中的作用：目的1：利用SAA基因敲除(KO)和过度表达的小鼠模型，评估SaaS在根尖周病变中的作用。目的2：确定SaaS的功能受体和信号转导途径。目的3：确定肥胖-糖尿病是否通过SaaS改变根尖周炎症。

DESCRIPTION (provided by applicant): Although infection of the dental pulp induces a periapical lesion, the course of this disease is also affected by host factors. For example long duration diabetics exhibited teeth with larger periapical lesions than short duration diabetics and healthy controls. To date, the relationships between bacterial pathogens/pathogen- associated molecular patterns (PAMPs) and the host immune system have been extensively investigated. However involvement of host-derived danger-associated molecular patterns (DAMPs), which are released by damaged cells, in periapical lesions is unknown. In our preliminary studies, SAA3 (Serum Amyloid A3), which is a DAMP, was the most highly up-regulated gene in rodent periapical lesions, and the SAA3 protein was strongly expressed in mouse periapical lesions. Systemic SAA levels are significantly elevated in a mouse diet-induced obesity model (DIO), in which animals develop pre-diabetes and steatosis (fatty liver) vs. control mice, indicating an association of SAA with obesity- induced systemic inflammation. In addition, infected DIO mice exhibited elevated serum SAA and had larger periapical lesions compared to controls, suggesting a pathologic link between SAA and periapical lesion severity. The central hypothesis of this proposal is that SAA, produced in response to dental infections, exacerbates dentoalveolar bone destruction, and furthermore contributes to systemic inflammation and its sequellae in obesity/type 2 diabetes. We propose that SAA is the primary DAMP in periapical lesions, and is a key enhancer of dentoalveolar inflammation. SAA is therefore an innovative target in modulating oral infection and inflammation. We will pursue the role of SAA in periapical lesions in the following three specific aims: AIM 1: To assess the role of SAAs in periapical lesions using SAA knockout (KO) and overexpression mouse models. Aim 2: To identify the functional receptors and signaling pathways for SAAs. AIM 3: To determine whether obesity-diabetes ('diabesity') alters periapical inflammation via SAAs.