Functional role of serum Amyloid A in periapical inflammation

描述（由申请人提供）：虽然牙髓感染引起根尖周病变，但这种疾病的病程也受宿主因素的影响。例如，长期糖尿病患者的牙齿根尖周病变比短期糖尿病患者大， 健康对照迄今为止，细菌病原体/病原体相关分子模式（PAMP）与宿主免疫系统之间的关系已被广泛研究。然而，在根尖周病变中，由受损细胞释放的宿主源性牙本质相关分子模式（DAMP）的参与尚不清楚。在我们的初步研究中，血清淀粉样蛋白A3（SAA 3），这是一个DAMP，是最高度上调的基因在啮齿动物根尖周病变，和SAA 3蛋白强烈表达在小鼠根尖周病变。全身SAA水平在小鼠饮食诱导的肥胖模型（DIO）中显著升高，其中动物相对于对照小鼠发展糖尿病前期和脂肪变性（脂肪肝），表明SAA与肥胖诱导的全身炎症相关。此外，感染的DIO小鼠表现出血清SAA升高，并有较大的根尖周病变相比，对照组，表明SAA和根尖周病变的严重程度之间的病理联系。该建议的中心假设是，SAA，响应于牙齿感染产生，加剧牙槽骨破坏，并进一步促进全身炎症及其在肥胖症/2型糖尿病中的后遗症。我们认为SAA是根尖周病变中的主要DAMP，并且是牙槽炎症的关键增强剂。因此，SAA是调节口腔感染和炎症的创新靶标。我们将追求SAA在根尖周病变中的作用，在以下三个具体目标：目的1：评估SAA在根尖周病变使用SAA敲除（KO）和过表达小鼠模型的作用。目的2：鉴定SAA的功能受体和信号通路。目的3：确定肥胖-糖尿病（“糖尿病”）是否通过SAA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.