A new Chinese herb-derived selective Toll-like receptor antagonist (Project 1)

一种新型中药选择性Toll样受体拮抗剂（项目1）

基本信息

批准号：
8460786
负责人：
Daping Fan
金额：
$ 20.55万
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：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460786
关键词：
Adaptor Signaling Protein Adhesions Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Arterial Fatty Streak Atherosclerosis Attenuated Binding Blood Vessels Cells China Chinese Herbs Chinese Traditional Medicine Chronic Clinic Clinical Trials Complementary and alternative medicine Data Deposition Development Diet Disease Endothelial Cells Fatty acid glycerol esters Herb Human In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-1 Invaded Investigation Leukocytes Ligands Lipids Lipopolysaccharides Low Density Lipoprotein Receptor Measures Mediating Molecular Mus Myocardial Infarction Natural Immunity Pharmacology Phenotype Plants Play Proteins Role Signal Transduction Smooth Muscle Myocytes Staging Stroke TLR2 gene TLR3 gene TLR4 gene Testing Therapeutic Therapeutic Agents Tissues Toll-like receptors United States Vascular Endothelial Cell Viral Work abstracting atherogenesis base cell motility dietary supplements driving force feeding hypercholesterolemia immune function inflammatory marker macrophage monocyte novel oxidized lipid pathogen receptor vascular inflammation

项目摘要

Abstract: Atherosclerosis is the direct cause of heart attack and stroke, the No. 1 and No. 3 killers in the United States, respectively. It is the result of both lipid deposition and chronic vascular inflammation. Toll-like receptors (TLRs), the key components of innate immunity, play detrimental roles in every stage of atherosclerosis, with TLR2 and TLR4 being best documented. While participating in the first line of defense against invading pathogens, TLR2- and TLR4-mediated signaling is considered to be a driving force in atherogenesis. Thus, blockade of TLR2 and TLR4 signaling is an intriguing therapeutic approach for atherosclerosis. However, no TLR2 or TLR4 antagonists are currently approved for clinic use. Recently, in an effort to isolate and characterize single compounds from Sparganium stoloniferum tubers, a commonly used Traditional Chinese Medicine herb, we obtained a novel compound, designated Sparstolonin B (SsnB), and made exciting discoveries. Our preliminary studies show that 1) SsnB has potent anti-inflammatory effects on macrophages by selectively blocking TLR2 and TLR4 signaling; 2) SsnB diminishes the ability of activated endothelial cells to attract monocytes for adhesion, and decreases arterial smooth muscle cell migration; and 3) SsnB effectively suppresses inflammatory response to lipopolysaccharide (LPS) in mice. On the basis of these preliminary data, we hypothesize that SsnB can be developed as an anti-inflammatory and anti-atherogenic agent by virtue of its selective inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose three specific aims. SA1. To elucidate the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. We will express and purify the Toll/IL-1 receptor (TIR) domains of TLRs, the adaptor proteins TIRAP/Mal and MyD88, and examine the binding of SsnB to these proteins. SA2. To examine the effects of SsnB on resident vascular cells. We will test the hypothesis that SsnB suppresses the inflammatory phenotype in arterial endothelial and smooth muscle cells by blocking TLR2 and TLR4 signaling. SA3. To test the hypothesis that SsnB attenuates atherogenesis in mice. LDL receptor (LDLR) deficient mice will be fed high fat diet to induce hypercholesterolemia and atherosclerosis. SsnB will be administrated to test if it attenuates atherogenesis in these mice. In summary, this study will test the anti-inflammatory and anti-atherogenic effects of a new natural compound recently isolated and characterized by us. The confirmation of the hypothesis that SsnB has anti-inflammatory and anti-atherogenic merit by blocking TLR2 and TLR4 signaling in macrophages and resident vascular cells will usher the development of this compound into an anti-atherogenic agent. This study will also provide a new example of complementary and alternative medicine bridging with modern pharmacology.

抽象的：动脉粥样硬化是心脏病发作和中风的直接原因，分别是美国的第一和第三杀手。这是脂质沉积和慢性血管炎症的结果。 Toll样受体（TLR）是先天免疫的关键组成部分，在动脉粥样硬化的每个阶段都起着不利的作用，最好记录TLR2和TLR4。在参与针对入侵病原体的第一道防线时，TLR2-和TLR4介导的信号被认为是动脉粥样硬化中的驱动力。因此，TLR2和TLR4信号传导的封锁是动脉粥样硬化的一种有趣的治疗方法。但是，目前尚无TLR2或TLR4拮抗剂用于临床使用。最近，为了隔离和表征来自一种常用的中国药物草药的Sparganium Stoloniferum块茎的单一化合物，我们获得了一种新型化合物，指定为Sparstolonin B（SSNB），并进行了令人兴奋的发现。我们的初步研究表明，1）SSNB通过选择性地阻断TLR2和TLR4信号传导对巨噬细胞具有有效的抗炎作用； 2）SSNB降低了活化的内皮细胞吸引单核细胞的能力，并降低了动脉平滑肌细胞的迁移； 3）SSNB有效抑制小鼠对脂多糖（LPS）的炎症反应。根据这些初步数据，我们假设SSNB可以通过其对TLR2和TLR4信号传导的选择性抑制作用而开发为一种抗炎和抗动脉粥样硬化剂。为了检验这一假设，我们提出了三个具体目标。 SA1。为了阐明SSNB阻止TLR2和TLR4信号传导的分子机制。我们将表达和纯化TLR的TOLL/IL-1受体（TIR）结构域，衔接蛋白Tirap/Mal和MyD88，并检查SSNB与这些蛋白质的结合。 SA2。检查SSNB对驻留血管细胞的影响。我们将通过阻断TLR2和TLR4信号传导来测试SSNB抑制动脉内皮和平滑肌细胞中炎症表型的假设。 SA3。测试SSNB减弱小鼠动脉粥样硬化的假设。 LDL受体（LDLR）缺乏小鼠将喂养高脂饮食，以诱导高胆固醇血症和动脉粥样硬化。 SSNB将被管理以测试它是否减弱了这些小鼠的动脉粥样硬化。总而言之，这项研究将测试一种新的天然化合物的抗炎和抗动脉粥样硬化作用，该化合物最近被我们分离和特征。证实了SSNB具有抗炎和抗动脉粥样硬化优点，通过阻止巨噬细胞中TLR2和TLR4信号传导具有抗炎和抗动脉粥样硬化的优点，这一假设将使该化合物的发育成长为抗动脉粥样硬化剂。这项研究还将提供一个与现代药理学桥接的互补和替代药物的新例子。