Functional role of serum Amyloid A in periapical inflammation

血清淀粉样蛋白 A 在根尖周炎症中的功能作用

• 批准号: 9390749
• 负责人: HAJIME SASAKI
• 金额: $ 40.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390749
• 关键词: Adenovirus Vector; Adult; Affect; Affinity; Amyloid; Animals; Backcrossings; Bacterial Infections; Binding; Binding Sites; Biological Assay; CD36 gene; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Dental; Dental Pulp; Development; Diabesity; Diabetes Mellitus; Diet; Disease; Down-Regulation; Enhancers; Exhibits; Expression Profiling; FPR2 gene; Fatty Liver; Gene Expression; Genes; Goals; Granulomatous; Histology; Immune system; Immunohistochemistry; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Integration Host Factors; Interleukin-1; Interleukin-10; Jaw; Kinetics; Knock-out; Knockout Mice; Knowledge; Lesion; Link; Liver Fibrosis; Mediating; Microarray Analysis; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral; Osteitis; Outcome; Palmitates; Pathogenesis; Pathogenicity; Pathologic; Pattern; Peptides; Play; Prediabetes syndrome; Prevalence; Process; Production; Proteins; Pulp Canals; Receptor Signaling; Recombinants; Research; Rodent; Role; Serum; Serum amyloid A protein; Severities; Signal Pathway; Site; Source; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Tooth Diseases; Tooth root structure; Tooth structure; Up-Regulation; bone; bone loss; cell injury; cytokine; diabetic; healing; human model; in vivo; innovation; macrophage; mouse model; neutralizing monoclonal antibodies; novel; oral infection; overexpression; pathogen; pathogenic bacteria; periapical; protein expression; public health relevance; receptor; response; targeted treatment; treatment strategy

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.

描述（申请人提供）：虽然牙髓感染会引起根尖周病变，但这种疾病的病程也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表现出更大的根尖周病变，并且 健康的控制。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得到广泛研究。然而，由受损细胞释放的宿主衍生的危险相关分子模式（DAMP）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DAMP，是啮齿类根尖周病变中上调程度最高的基因，并且SAA3蛋白在小鼠根尖周病变中强烈表达。在饮食诱导的肥胖小鼠模型 (DIO) 中，与对照小鼠相比，动物出现糖尿病前期和脂肪变性（脂肪肝），全身 SAA 水平显着升高，表明 SAA 与肥胖诱导的全身炎症有关。此外，与对照组相比，受感染的 DIO 小鼠表现出血清 SAA 升高，并且根尖周病变更大，表明 SAA 与根尖周病变严重程度之间存在病理联系。该提议的中心假设是，针对牙齿感染而产生的 SAA 会加剧牙槽骨破坏，并进一步导致肥胖/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 DAMP，并且是牙槽骨炎症的关键促进剂。因此，SAA 是调节口腔感染和炎症的创新靶点。我们将通过以下三个具体目标来研究 SAA 在根尖周病变中的作用： 目标 1：使用 SAA 敲除（KO）和过表达小鼠模型评估 SAA 在根尖周病变中的作用。目标 2：确定 SAA 的功能受体和信号通路。目标 3：确定肥胖-糖尿病（“糖尿病”）是否通过 SAA 改变根尖周炎症。