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SsnB, a Chinese herb-derived selective TLR antagonist

SsnB，一种中药来源的选择性 TLR 拮抗剂

基本信息

批准号：
8453362
负责人：
Daping Fan
金额：
$ 16.61万
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：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453362
关键词：
Acute Adaptor Signaling Protein Alternative Therapies Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Attenuated Autoimmune Process Bacteria Binding Blood Books Cell membrane Cells China Chinese Herbs Chinese Traditional Medicine Chronic Clinic Clinical Colitis Complementary and alternative medicine Dendritic Cells Development Diabetes Mellitus Disease Dose Drug Design Endotoxemia Escherichia coli Future Herb Homologous Gene Immune In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 Invaded Investigation Language Lead Lentivirus Vector Leucine-Rich Repeat Ligands Mammalian Cell Measures Mediating Membrane Methods Modality Modern Medicine Molecular Monitor Mus Natural Immunity Organ Organism Pain Pathogenesis Pharmacology Plants Plasma Production Proteins Publishing Qi Receptor Signaling Research Sepsis Signal Pathway Signal Transduction Site Structure Survival Rate System Systemic Lupus Erythematosus TLR1 gene TLR2 gene TLR3 gene TLR4 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Effect Tissues Toll-like receptors Toxic effect Translating Virus Work base cytokine efficacy testing human TLR3 protein immune function improved in vivo insight macrophage mouse model novel overexpression pathogen protein protein interaction public health relevance receptor response small molecule stable cell line viral RNA

项目摘要

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are key components of innate immunity; they serve as the first line of defense against invading pathogens such as bacteria and viruses. The signaling initiated by TLRs is a double- edged sword. On the one hand, it may lead to confining or eliminating the invading organisms; on the other hand, a prolonged and exaggerated response can cause tissue and organ damage. Moreover, TLR signaling triggered by exogenous or endogenous ligands contributes to the pathogenesis of many chronic inflammatory diseases. For example, TLR2 and TLR4 are involved in atherosclerosis, autoimmune colitis, SLE, diabetes and Alzheimer's disease. Therefore, blockade of excessive TLR signaling is a therapeutic approach being pursued for these diseases. However, currently there are no approved TLR antagonists for clinic use. A Chinese herb, Sparganium stoloniferum has long been used in Traditional Chinese Medicine (TCM) for the treatment of several inflammatory diseases. Although much work has been done with extracts from this herb, no in-depth molecular investigation of its components has been performed. Recently, in an effort to isolate and functionally characterize single compounds from Sparganium stoloniferum tubers, we identified a novel compound, Sparstolonin B (SsnB) that selectively blocks TLR2- and TLR4-mediated signaling. This R21 proposal is aimed at continuing this exciting developmental research. The central hypothesis is that SsnB can be developed as an anti-inflammatory agent by virtue of its selective inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose two specific aims. SA1. To evaluate the toxicity and the anti- inflammatory efficacy of SsnB in vivo. We will first evaluate the in vivo toxicity of SsnB and then test if SsnB can suppress the inflammatory responses in endotoxemia and sepsis mouse models. SA2. To further elucidate the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. We will identify the acting sites of SsnB on TLR2 and TLR4 signaling pathways. These studies will provide mechanistic insights into the therapeutic effects of Sparganium stoloniferum tubers in inflammatory diseases, translating a centuries-old alternative therapy modality into modern pharmacology. The identification and confirmation of SsnB as a TLR2 and TLR4 antagonist will provide an opportunity to develop a new anti-inflammatory agent. In future studies, we will test the therapeutic value of SsnB for several immune-related chronic inflammatory diseases such as atherosclerosis and diabetes.

描述（申请人提供）：Toll 样受体（TLR）是先天免疫的关键组成部分；它们是抵御细菌和病毒等病原体入侵的第一道防线。 TLR 发起的信号传递是一把双刃剑。一方面，它可能导致限制或消灭入侵生物；另一方面，长时间且过度的反应会导致组织和器官损伤。此外，外源或内源配体触发的 TLR 信号传导有助于许多慢性炎症性疾病的发病机制。例如，TLR2和TLR4与动脉粥样硬化、自身免疫性结肠炎、SLE、糖尿病和阿尔茨海默病有关。因此，阻断过度的 TLR 信号传导是这些疾病的治疗方法。然而，目前尚无批准用于临床的TLR拮抗剂。三棱是一种中草药，长期以来在中医 (TCM) 中用于治疗多种炎症性疾病。尽管人们对这种草药的提取物进行了大量研究，但尚未对其成分进行深入的分子研究。最近，为了从三棱块茎中分离和功能表征单一化合物，我们鉴定了一种新化合物，Sparstolonin B (SsnB)，它可以选择性阻断 TLR2 和 TLR4 介导的信号传导。 R21 提案旨在继续这项令人兴奋的开发研究。核心假设是，SsnB 凭借其对 TLR2 和 TLR4 信号传导的选择性抑制作用，可以开发为抗炎剂。为了检验这一假设，我们提出了两个具体目标。 SA1。评价SsnB的体内毒性和抗炎功效。我们将首先评估 SsnB 的体内毒性，然后测试 SsnB 是否可以抑制内毒素血症和脓毒症小鼠模型中的炎症反应。 SA2。进一步阐明SsnB阻断TLR2和TLR4信号传导的分子机制。我们将确定 SsnB 对 TLR2 和 TLR4 信号通路的作用位点。这些研究将为三棱块茎对炎症性疾病的治疗作用提供机制见解，将具有数百年历史的替代疗法转化为现代药理学。 SsnB作为TLR2和TLR4拮抗剂的鉴定和确认将为开发新的抗炎剂提供机会。在未来的研究中，我们将测试SsnB对动脉粥样硬化和糖尿病等几种免疫相关慢性炎症性疾病的治疗价值。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chinese Herbal Compounds for the Prevention and Treatment of Atherosclerosis: Experimental Evidence and Mechanisms.

DOI：
10.1155/2015/752610
发表时间：
2015
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
0
作者：
Liu Q;Li J;Hartstone-Rose A;Wang J;Li J;Janicki JS;Fan D
通讯作者：
Fan D

Effects and mechanisms of chinese herbal medicine in ameliorating myocardial ischemia-reperfusion injury.

DOI：
10.1155/2013/925625
发表时间：
2013
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
0
作者：
Liu Q;Li J;Wang J;Li J;Janicki JS;Fan D
通讯作者：
Fan D

Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs.

DOI：
10.1007/s10549-014-3164-7
发表时间：
2014-11
期刊：
BREAST CANCER RESEARCH AND TREATMENT
影响因子：
3.8
作者：
Jia, Xuemei;Yu, Fang;Wang, Junfeng;Iwanowycz, Stephen;Saaoud, Fatma;Wang, Yuzhen;Hu, Jun;Wang, Qian;Fan, Daping
通讯作者：
Fan, Daping

Sparstolonin B, a novel plant derived compound, arrests cell cycle and induces apoptosis in N-myc amplified and N-myc nonamplified neuroblastoma cells.