Infection and Inflammation in Atherosclerosis

动脉粥样硬化中的感染和炎症

基本信息

批准号：
8888634
负责人：
Salomon Amar
金额：
$ 52.75万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888634
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Adverse effects Affect Alveolar Bone Loss Amino Acids Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Therapy Aorta Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Biochemical Biological Biological Assay Blood Circulation Bone Marrow Bone Resorption Carbohydrates Cells Cholesterol Chronic Clinical Clinical Trials Communicable Diseases Coronary Arteriosclerosis Data Development Diet Disease Disease Management Dose Drug Kinetics Epidemiologic Studies Exposure to Funding Goals Gram-Negative Bacteria Human Hypertension In Vitro Incidence Individual Infection Inflammation Inflammatory Intervention Lead Lesion Link Lipids Lung MAPK10 gene Maximum Tolerated Dose Mediating Medical Metabolic Microbe Modeling Modification Molecular Molecular Target Morbidity - disease rate Mus Myocardial Infarction Nucleotides Oral Osteogenesis Pathway interactions Patients Pattern Pattern recognition receptor Peptidoglycan Periodontal Diseases Periodontal Infection Pharmaceutical Chemistry Porphyromonas gingivalis Positioning Attribute Preclinical Testing Production Property Refractory Regulation Research Risk Factors Role Saline Serum Signal Pathway Signal Transduction Pathway Smoking Solubility Structure Structure-Activity Relationship TNF gene Testing Therapeutic Tissues Toll-like receptors Toxicology Transcription Factor AP-1 Tumor Necrosis Factor-alpha Valsalva sinus Variant analog atherogenesis base bone loss chemical stability cytokine cytotoxicity experience hypercholesterolemia improved interest macrophage member mortality novel pathogen prevent public health relevance receptor scaffold screening therapeutic target vascular inflammation

项目摘要

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.

描述（由适用提供）：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（例如牙周感染）上是CAD的潜在促进者，因为传统的危险因素，包括高胆固醇血症，吸烟和高血压，无法完全解释CAD的事件。流行病学研究表明，牙周感染的个体患有CAD的可能性高30％至100％。在过去的融资周期中，我们的发现将NOD2，牙龈牙龈毒死膜（P.G.），APOE和脂肪饮食与骨质流失和动脉粥样硬化的炎症变化有关。 APOE - / - 小鼠注射了腹腔使用MDP刺激NOD2并每周口服P.G.在15周内，与APOE - / - 小鼠相比，在主动脉和主动脉鼻窦窦中降低了血清胆固醇，炎性细胞因子，肺泡骨质流失和动脉粥样硬化病变的降低。但注射了盐水。该模型中的NOD2缺乏可显着汇总骨质流失和动脉粥样硬化。尽管MDP是治疗发现的有趣靶标，但肯定需要具有较高抗炎活性（例如TNF）和增强的药代动力学稳定性的类似物。当前抗TNF-抗体疗法的副作用进一步证明了这一点。我们最近生成了新型的MDP类似物，并确定了具有显着抗TNF和NFB特性的候选者。主动MDP类似物将用于帮助表征负责MDP抗炎特性的途径。为了检验我们的假设，我们提出了以下目的：目标1。优化MDP的生物学活性：我们将继续进行药物化学和生化筛查工作，以获得选择性抗炎的MDP化合物并优化基于MDP的几个脚手架。 AIM 2。确定MDP和MDP类似物的信号通路；目标3。优化化合物的临床前测试：在我们的牙周疾病（PD）和动脉粥样硬化的鼠模型中，将测试在体外发现的有限数量的MDP类似物。我们的目标是阐明优化MDP化合物的作用机理，这是迈向识别适合临床发育的新型抗炎化合物的一步。这将使我们能够在我们拥有丰富经验的人类临床试验环境中运用这种理解。