Infection and Inflammation in Atherosclerosis

 描述(申请人提供)：冠状动脉疾病(CAD)是世界范围内发病率和死亡率的主要原因。由于包括高胆固醇血症、吸烟和高血压在内的传统危险因素不能完全解释冠心病的发生，近年来人们对慢性感染性疾病，如牙周感染，作为冠心病的潜在贡献者的兴趣日益集中。流行病学研究表明，患有牙周感染的人患冠心病的可能性要高出30%到100%。在过去的资金周期中，我们的发现将NOD2、口服牙龈卟啉单胞菌(P.G.)、载脂蛋白E(ApoE)和脂肪饮食与骨丢失和动脉粥样硬化的炎症变化联系起来。APOE-/-小鼠ip。用MDP刺激NOD2，每周一次口服P.G.与口服P.G.的ApoE-/-小鼠相比，15周的ApoE-/-小鼠的血清胆固醇、炎症细胞因子、牙槽骨丢失以及主动脉和主动脉窦的动脉粥样硬化病变都有所减少。但注射了生理盐水。该模型中NOD2缺乏明显加重了骨丢失和动脉粥样硬化。虽然MDP是治疗发现的一个有趣的靶点，但具有更高抗炎活性(如肿瘤坏死因子)和增强药代动力学稳定性的类似物肯定是必要的。目前的抗肿瘤坏死因子-抗体疗法的副作用进一步证明了这一点。我们最近产生了新的亚甲基二磷酸类似物，并确定了一种具有显著抗肿瘤坏死因子和核因子B特性的候选者。活性MDP类似物将被用来帮助表征负责MDP抗炎特性的途径。为了验证我们的假设，我们提出了以下目标：目的1.优化亚甲基二磷酸核苷的生物活性：我们将继续药物化学和生化筛选工作，以获得选择性抗炎的亚甲基二磷酸核苷化合物(S)，并优化几种基于亚甲基二磷酸核苷的支架材料。目的2.确定MDP和MDP类似物的信号通路；以及目的3.优化化合物的临床前测试：将在我们的牙周病(PD)和动脉粥样硬化的小鼠模型中测试在体外发现的有限数量的MDP类似物能有力地减少肿瘤坏死因子的产生。我们的目标是阐明优化的MDP化合物的作用机制，朝着识别适合临床开发的新型抗炎化合物迈出一步。这将使我们能够将这一理解应用于人类临床试验环境，在那里我们有相当多的经验。

 DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent interest has focused on chronic infectious diseases such as periodontal infection as potential contributors to CAD since traditional risk factors including hypercholesterolemia, smoking, and hypertension fail to fully explain the incidence of CAD. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD. During the past funding cycle, our findings linked NOD2, exposure to oral Porphyromonas gingivalis (P.g.), ApoE, and fatty diets with inflammatory changes to both bone loss and atherosclerosis. ApoE-/- mice injected i.p. with MDP to stimulate NOD2 and given weekly oral gavage of P.g. for 15 weeks displayed a reduction of serum cholesterol, inflammatory cytokines, alveolar bone loss, and atherosclerotic lesions in the aorta and aortic sinus compared with ApoE-/- mice orally challenged with P.g. but injected with saline. NOD2 deficiency in this model significantly aggravated bone loss and atherosclerosis. While MDP is an interesting target for therapeutic discovery, analogs with higher anti-inflammatory activity (e.g.TNF) and enhanced pharmacokinetic stability are certainly required. This is further justified by the side effects of the current anti-TNF- antibody therapies. We have recently generated novel MDP analogs and identified a candidate with significant anti-TNF and NFB properties. Active MDP analogs will be used to help characterize the pathway responsible for the MDP anti-inflammation property. To test our hypothesis we propose the following aims: Aim 1. Optimizing biological activity of MDP: We will continue medicinal chemistry and biochemical screening efforts to obtain a selective anti-inflammatory MDP compound(s) and optimize several scaffolds based on MDP. Aim 2. Determine signaling pathways of MDP and MDP analogs; and Aim 3. Preclinical testing of optimized compounds: A limited number of MDP analogs found in vitro to robustly reduce TNF production will be tested in our murine models of periodontal disease (PD) and atherosclerosis. Our goal is to elucidate the mechanism of action of optimized MDP compounds, a step towards identifying novel anti-inflammatory compounds suitable for clinical development. This will position us to apply this understanding in a human clinical trial setting, where we have considerable experience.