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Sparstolonin B as an anti-atherogenic agent

Sparstolonin B 作为抗动脉粥样硬化剂

基本信息

批准号：
8419003
负责人：
Daping Fan
金额：
$ 35.43万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8419003
关键词：
Adaptor Signaling Protein Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Apolipoprotein E Arterial Fatty Streak Atherosclerosis Attenuated Binding Blood Vessels Cardiovascular system Cells Chinese Herbs Chinese Traditional Medicine Cholesterol Chronic Clinic Clinical Collagen Coronary Data Databases Deposition Development Diet Disease Endothelial Cells Event Fatty acid glycerol esters Human Hyperlipidemia Immune system Infiltration Inflammation Inflammatory Inflammatory Response Invaded Lentivirus Vector Leukocytes Ligands Lipids Lipopolysaccharides Measures Mediating Molecular Monitor Mus Myocardial Infarction Natural Immunity Phenotype Play Proteins Publishing Role Serum Signal Transduction Site Smooth Muscle Myocytes Stroke TLR2 gene TLR4 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Tissues Toll-Like Receptor 2 Toll-like receptors Toxic effect Vascular Endothelial Cell Viral analog atherogenesis base cell motility driving force feeding hypercholesterolemia in vivo inflammatory marker macrophage monocyte mutant novel oxidized lipid pathogen protein protein interaction public health relevance research study response scaffold screening stable cell line success vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the result of both lipid deposition and chronic vascular inflammation. However, a defined causal role for inflammation in atherogenesis is elusive, largely because of the lack of a clinical success of anti- inflammatory agents in atherosclerosis control. Nevertheless, evidence of the participation of the immune system, especially the key components of innate immunity, Toll-like receptors (TLRs), holds strong in experimental atherosclerosis. Over a dozen TLRs have been identified so far, most of them expressed in atheroma cells, with TLR2 and TLR4 being best documented. Blockade of TLR2 and TLR4 signaling is an intriguing therapeutic approach for atherosclerosis. However, the development of TLR antagonists as therapeutic agents has been surprisingly slow, and no TLR2 or TLR4 antagonists are currently approved for clinic use. Recently, we identified a natural compound Sparstolonin B (SsnB) as an antagonist for TLR2 and TLR4. Our recently published data and new preliminary studies show that: 1) SsnB has potent anti-inflammatory effects on macrophages by selectively blocking TLR2 and TLR4 signaling; 2) SsnB interrupts the recruitment of MyD88 to TLR2 and TLR4; 3) SsnB diminishes the ability of activated arterial endothelial cells to attract monocytes, and decreases arterial smooth muscle cell migration; and 4) SsnB effectively suppresses inflammatory response to lipopolysaccharide in mice. On the basis of these data, we hypothesize that SsnB can attenuate atherogenesis by virtue of its inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose three specific aims: SA1. To test the hypothesis that SsnB attenuates atherogenesis in mice; SA2. To test the hypothesis that SsnB mitigates inflammation in vascular cells by blocking TLR2 and TLR4 signaling; and SA3. To determine the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. The confirmation of the hypothesis will usher the development of SsnB as a new anti-atherogenic agent; it will also provide a pharmacological evidence for the causal role of TLR2 and TLR4 signaling in atherogenesis.

描述（由申请人提供）：动脉粥样硬化是脂质沉积和慢性血管炎症的结果。然而，炎症在动脉粥样硬化形成中的确定的因果作用是难以捉摸的，主要是因为抗炎剂在动脉粥样硬化控制中缺乏临床成功。然而，免疫系统参与的证据，特别是先天免疫的关键成分，Toll样受体（TLR），在实验性动脉粥样硬化中具有很强的作用。迄今为止，已经鉴定了十几种TLR，其中大多数在动脉粥样硬化细胞中表达，TLR 2和TLR 4被最好地记录。TLR 2和TLR 4信号传导的阻断是动脉粥样硬化的一种有趣的治疗方法。然而，TLR拮抗剂作为治疗剂的开发令人惊讶地缓慢，并且目前没有TLR 2或TLR 4拮抗剂被批准用于临床使用。最近，我们鉴定了一种天然化合物Sparstolonin B（Ssn B）作为TLR 2和TLR 4的拮抗剂。我们最近发表的数据和新的初步研究表明：1）SsnB通过选择性阻断TLR 2和TLR 4信号传导对巨噬细胞具有强的抗炎作用; 2）SsnB中断MyD 88向TLR 2和TLR 4的募集; 3）SsnB降低活化的动脉内皮细胞吸引单核细胞的能力，并减少动脉平滑肌细胞的迁移; SsnB能有效地抑制小鼠对脂多糖的炎症反应。基于这些数据，我们假设SsnB可以通过其对TLR 2和TLR 4信号传导的抑制作用来减轻动脉粥样硬化形成。为了验证这一假设，我们提出了三个具体目标：SA 1。为了检验SsnB减弱小鼠动脉粥样硬化形成的假设; SA 2.检验SsnB通过阻断TLR 2和TLR 4信号传导减轻血管细胞炎症的假设;和SA 3.确定SsnB阻断TLR 2和TLR 4信号传导的分子机制。这一假说的证实将为SsnB作为一种新的抗动脉粥样硬化药物的开发奠定基础，同时也为TLR 2和TLR 4信号通路在动脉粥样硬化形成中的作用提供了药理学证据。