"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：
9273596
负责人：
Salomon Amar
金额：
$ 53.62万
依托单位：
NEW YORK MEDICAL COLLEGE
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/9273596
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 Exposure to Funding Goals Gram-Negative Bacteria Human Hypertension In Vitro Incidence Individual Infection Inflammation Inflammatory Injectable 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 Pathogenicity Pathway interactions Patients Pattern Pattern recognition receptor Peptidoglycan Periodontal Diseases Periodontal Infection Permeability Pharmaceutical Chemistry Pharmacology 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 Valsalva sinus Variant analog atherogenesis base bone loss chemical stability clinical development cytokine cytotoxicity epidemiology study experience hypercholesterolemia improved interest macrophage member mortality mouse model novel novel therapeutic intervention pathogen prevent public health relevance receptor scaffold screening targeted treatment 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（由申请人提供）：冠状动脉疾病（CAD）是全世界发病和死亡的主要原因，因为传统的危险因素包括高胆固醇血症、吸烟和心脏病，最近的兴趣集中在牙周感染等慢性传染病上。高血压无法完全解释 CAD 的发病率。流行病学研究表明，在过去的资助周期中，牙周感染患者患 CAD 的可能性增加 30% 至 100%。 NOD2、暴露于口腔牙龈卟啉单胞菌 (P.g.)、ApoE 和脂肪饮食会导致骨质流失和动脉粥样硬化的炎症变化，腹膜内注射 MDP 刺激 NOD2 并每周口服 P.g.减少血清胆固醇、炎性细胞因子、牙槽骨丢失以及主动脉和动脉粥样硬化病变与口服P.g但注射NOD2缺陷的ApoE-/-小鼠相比，在该模型中，主动脉窦显着加重了骨质流失和动脉粥样硬化，而具有更高抗炎活性的类似物（例如TNF）则显着加剧了骨质流失和动脉粥样硬化。）和增强的药代动力学稳定性当然是必需的，当前抗 TNF-α 抗体疗法的副作用进一步证明了这一点，我们最近生成并鉴定了新型 MDP 类似物。具有显着抗 TNF 和 NFκB 特性的候选物将用于帮助表征 MDP 抗炎特性的途径。为了检验我们的假设，我们提出以下目标：目标 1. 优化 MDP 的生物活性。 MDP：我们将继续进行药物化学和生化筛选工作，以获得选择性抗炎MDP化合物，并基于MDP优化几种支架。确定MDP和MDP的信号通路。目标 3. 优化化合物的临床前测试将在我们的牙周病 (PD) 和动脉粥样硬化小鼠模型中测试体外发现的有限数量的 MDP 类似物，以显着减少 TNF 的产生。优化的 MDP 化合物的作用，是识别适合临床开发的新型抗炎化合物的一步，这将使我们能够将这种理解应用到我们拥有丰富经验的人体临床试验环境中。