The Effect of Statin on Diabetes-Associated Peridontal Disease

他汀类药物对糖尿病相关牙周疾病的影响

• 批准号: 7987928
• 负责人: Yan Huang
• 金额: $ 36.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987928
• 关键词: Academy; Address; Alveolar Bone Loss; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cholesterol; Chronic Disease; Clinical; Clinical Research; Complications of Diabetes Mellitus; Diabetes Mellitus; Disease; Dyslipidemias; Educational workshop; Event; Extracellular Signal Regulated Kinases; FOS gene; Funding; Gingival Crevicular Fluid; Glucose; Goals; Immune response; Inflammation; Inflammatory; Inflammatory Response; Investigation; JUN gene; Lead; Lipopolysaccharides; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Molecular; Molecular Biology; Mononuclear; National Institute of Dental and Craniofacial Research; Pathogenesis; Pathway interactions; Patients; Periodontal Diseases; Periodontium; Pharmaceutical Preparations; Play; Research Project Grants; Risk; Role; Signal Transduction; Simvastatin; Testing; Tissues; Tooth Loss; Transcription Factor AP-1; Transcriptional Regulation; base; cardiovascular disorder risk; cytokine; diabetic; diabetic patient; high risk; hypercholesterolemia; improved; inflammatory marker; non-diabetic; novel; prevent; public health relevance

DESCRIPTION (provided by applicant): The recent workshop on inflammation and periodontal diseases organized by American Academy of Periodontology (AAP) has proposed "use of statins and targeted anti-inflammatory therapies in patients with periodontal disease to modulate inflammation and, hence, lower risk for systemic conditions such as atherosclerosis" as one of the clinical initiatives in the medium term (5 to 10 years). Although a recent study has shown that patients with periodontal disease who were taking statins had significantly less diseased periodontal tissue than those who weren't on the drugs, it remains unknown how statin use is associated with periodontal disease in diabetic patients. The study in diabetic patients is important since periodontal disease is more prevalent and severe in diabetic patients than that in nondiabetic patients. Furthermore, it remains unknown how statin use is associated with periodontal expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that are essential for developing periodontal disease. From our recent NIDCR-funded study, we found that high glucose amplified lipopolysaccharide (LPS)-elicited immune responses from mononuclear cells. We also found that simvastatin effectively suppresses high glucose-boosted, LPS-induce expression of inflammatory cytokines and MMPs. In addition, in our studies to explore the molecular mechanisms involved in statin's action, we found that statin inhibited high glucose and LPS- stimulated transcription factor AP-1 activity, which is critical for MMP expression. However, it remains unclear how statin inhibits AP-1 activity. Based on these findings, we proposed three specific aims: 1. To determine the effects of simvastatin on periodontal inflammation and alveolar bone loss in nondiabetic and diabetic animal models. 2. To determine the relationship between statin use and periodontal disease as well as periodontal inflammatory cytokine and MMP expression in nondiabetic and diabetic patients. 3. To determine the signaling and molecular mechanisms by which statin inhibits high glucose/LPS-stimulated transcription factor AP-1 activity in mononuclear cells. We hypothesize that statin administration is associated with a reduction of periodontal tissue inflammation in both nondiabetic and diabetic animals and patients, but the reduction in diabetic patients is greater. We also hypothesize that statin inhibits AP-1 activity by blocking expression and activation of c-Fos. The goal of this research project is to provide novel information for better understanding of the effects of statin on periodontal disease in both nondiabetic and diabetic patients, which is important for potential use of statins in treatment of periodontal disease as proposed by AAP. PUBLIC HEALTH RELEVANCE: By combining animal, patient and molecular biology studies, the goal of this research project is to provide novel information for better understanding of anti-inflammatory effects of statin on periodontal disease and tissue inflammation in both nondiabetic and diabetic patients, which is essential for clinical use of statins in the treatment of periodontal disease as proposed by American Academy of Periodontology as one of the clinical initiatives in the medium term (5 to 10 years).

描述（由申请人提供）：美国牙周病学学院（AAP）组织的炎症和牙周疾病的最新研讨会提议“使用毒素和牙周疾病患者的靶向抗炎疗法的使用来调节临时性启动（临时性启发）的系统性较低（例如，较低）对全身性状况的风险较低。尽管最近的一项研究表明，接受他汀类药物的牙周疾病患者的牙周组织明显小于不接受药物的患者，但尚不清楚他汀类药物的使用与糖尿病患者中如何与牙周疾病有关。糖尿病患者的研究很重要，因为糖尿病患者的牙周疾病比非糖尿病患者更普遍和严重。此外，尚不清楚他汀类药物的使用与炎性细胞因子和基质金属蛋白酶（MMP）的牙周表达如何相关，这对于发展牙周疾病至关重要。从我们最近的NIDCR资助研究中，我们发现高葡萄糖扩增的脂多糖（LPS）来自单核细胞的免疫反应。我们还发现，辛伐他汀可以有效抑制炎症细胞因子和MMP的高葡萄糖诱导的高葡萄糖表达。此外，在探索他汀类药物作用的分子机制的研究中，我们发现他汀类药物抑制了高葡萄糖和LPS刺激的转录因子AP-1活性，这对于MMP表达至关重要。但是，尚不清楚他汀类药物如何抑制AP-1活性。基于这些发现，我们提出了三个具体目的：1。确定辛伐他汀对非糖尿病和糖尿病动物模型中牙周炎症和肺泡骨质流失的影响。 2。确定他汀类药物使用与牙周疾病之间的关系，以及牙周炎症性细胞因子和非糖尿病患者的MMP表达。 3。确定他汀类药物抑制单核细胞中高葡萄糖/LPS刺激的转录因子AP-1活性的信号传导和分子机制。我们假设汀类药物给药与非糖尿病和糖尿病动物和患者的牙周组织炎症的减少有关，但是糖尿病患者的减少量更大。我们还假设他汀类药物通过阻止C-FOS的表达和激活来抑制AP-1活性。该研究项目的目的是提供新的信息，以更好地理解他汀类药物对非糖尿病和糖尿病患者牙周疾病的影响，这对于AAP提出的汀类药物在治疗牙周疾病中的潜在使用很重要。 公共卫生相关性：通过将动物，患者和分子生物学研究结合起来，该研究项目的目的是提供新的信息，以更好地理解他汀类药物对非糖尿病患者牙他汀类药物对牙周疾病和组织炎症的抗炎作用，这对于拟议中培训学学院的临床学临床学临床是一项周期性的临床学，这对于在周期性疾病中均可在周期性疾病中临床临床临床（该临床学）临床（该培训）临床启动（该临床学）的临床学至关重要。