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：
9207092
负责人：
Daping Fan
金额：
$ 34.54万
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 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207092
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 Deposition Development Diet Disease Endothelial Cells Event High Fat Diet Human Hyperlipidemia Immune system Infiltration Inflammation Inflammatory Inflammatory Response Injectable Interruption Invaded Lentivirus Vector Leukocytes Ligands Lipids Lipopolysaccharides Measures Mediating Molecular Monitor Mus Myocardial Infarction Natural Immunity Peritoneal Pharmacology Phenotype Play Proteins Publishing Recruitment Activity Role Serum Signal Transduction Site Smooth Muscle Myocytes Stroke TIRAP gene TLR2 gene TLR4 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Tissues Toll-like receptors Toxic effect Vascular Endothelial Cell Viral analog antiatherogenic agent atherogenesis cell motility driving force experimental study hypercholesterolemia in vivo inflammatory marker macrophage monocyte mutant novel oxidized lipid pathogen protein protein interaction public health relevance 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明确因果作用尚不清楚，这主要是因为抗炎药物在控制动脉粥样硬化方面缺乏临床成功。尽管如此，免疫系统参与的证据，特别是先天免疫的关键组成部分，Toll 样受体 (TLR)，在实验性动脉粥样硬化中仍然存在强有力的证据。迄今为止，已鉴定出十多个 TLR，其中大多数在动脉粥样硬化细胞中表达，其中 TLR2 和 TLR4 的记录最为详尽。阻断 TLR2 和 TLR4 信号传导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却出人意料地缓慢，目前还没有TLR2或TLR4拮抗剂被批准用于临床。最近，我们鉴定了一种天然化合物 Sparstolonin B (SsnB) 作为 TLR2 和 TLR4 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 TLR2 和 TLR4 信号传导，对巨噬细胞具有有效的抗炎作用； 2) SsnB 中断 MyD88 向 TLR2 和 TLR4 的招募； 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； 4) SsnB 有效抑制小鼠对脂多糖的炎症反应。根据这些数据，我们假设 SsnB 可以通过其对 TLR2 和 TLR4 信号传导的抑制作用来减弱动脉粥样硬化形成。为了检验这个假设，我们提出了三个具体目标：SA1。检验 SsnB 减轻小鼠动脉粥样硬化形成的假设； SA2。检验 SsnB 通过阻断 TLR2 和 TLR4 信号传导减轻血管细胞炎症的假设；和SA3。确定 SsnB 阻断 TLR2 和 TLR4 信号传导的分子机制。该假设的证实将引领SsnB作为新型抗动脉粥样硬化药物的发展；它还将为 TLR2 和 TLR4 信号传导在动脉粥样硬化形成中的因果作用提供药理学证据。