Infection and Inflammation in Atherosclerosis

 描述（由申请人提供）：冠状动脉疾病（CAD）是全球发病率和死亡率的主要原因。最近的兴趣集中在慢性感染性疾病，如牙周感染作为CAD的潜在贡献者，因为传统的风险因素，包括高胆固醇血症，吸烟和高血压不能完全解释CAD的发病率。流行病学研究表明，牙周感染的个体患CAD的可能性增加30%至100%。在过去的资助周期中，我们的研究结果将NOD 2，暴露于口腔牙龈卟啉单胞菌（P.g.），ApoE和脂肪饮食与骨丢失和动脉粥样硬化的炎症变化。ApoE-/-小鼠腹膜内注射MDP以刺激NOD 2，每周口服管饲P.g. 15周的ApoE-/-小鼠的血清胆固醇、炎性细胞因子、牙槽骨丢失以及主动脉和主动脉窦中的动脉粥样硬化病变的减少。但注射了生理盐水NOD 2缺乏可加重骨丢失和动脉粥样硬化。虽然MDP是一个有趣的治疗发现的目标，具有更高的抗炎活性（如TNF）和增强的药代动力学稳定性的类似物肯定是需要的。这进一步被当前抗TNF-α抗体疗法的副作用证明。我们最近产生了新的MDP类似物，并确定了一个候选人具有显着的抗TNF和NF κ B B的属性。活性MDP类似物将用于帮助表征负责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：目标1。优化MDP的生物活性：我们将继续药物化学和生物化学筛选工作，以获得选择性抗炎MDP化合物，并优化基于MDP的几种支架。目标二。确定MDP和MDP类似物的信号传导途径;和优化化合物的临床前测试：将在我们的牙周病（PD）和动脉粥样硬化小鼠模型中测试体外发现的有限数量的MDP类似物，以稳健地减少TNF的产生。我们的目标是阐明优化的MDP化合物的作用机制，这是确定适合临床开发的新型抗炎化合物的一步。这将使我们能够在人类临床试验环境中应用这种理解，我们在这方面有相当丰富的经验。

 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.