Signaling mediators of CCL2/CCR2 and natural product discovery

CCL2/CCR2 信号传导介质和天然产物发现

• 批准号: 10623540
• 负责人: Piwen Wang
• 金额: $ 36.08万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623540
• 关键词: Adipocytes; Anti-Inflammatory Agents; Antioxidants; Area; Atherosclerosis; Binding; Biological Availability; CCL2 gene; Cardiovascular Diseases; Cells; Chronic Disease; Clinical Trials; Compensation; Development; Diabetes Mellitus; Disease; Disease model; Dose; Drug Kinetics; Endothelial Cells; Enzymes; Event; Family; Fibroblasts; G-Protein-Coupled Receptors; Goals; Greater Burdock; Herb; Human; Immune; In Vitro; Inflammation; Inflammatory; Knowledge; Laboratories; Leukocytes; Ligands; Lignans; Malignant Neoplasms; Mediator; Molecular; Molecular Target; Natural Compound; Natural Products; Obesity; Osteoporosis; Pathogenesis; Patients; Pharmaceutical Preparations; Phytochemical; Prevention; Preventive; Quality of life; Reaction; Research; Signal Pathway; Signal Transduction; Source; Therapeutic Agents; Viral; Vision; arctigenin; cancer cell; cancer type; cell motility; chemokine; chemokine receptor; cytokine; disorder control; disorder prevention; improved; in vivo; inhibitor; interest; loss of function; monocyte chemoattractant protein 1 receptor; neoplastic cell; nervous system disorder; novel; pre-clinical; programs; prostate cancer model; recruit

Project Summary/Abstract Chemokines are a family of small cytokines best known for their ability to guide directed migration of cells expressing corresponding chemokine receptors. In addition to their activities in recruiting leukocytes for inflammatory reactions, emerging evidence has revealed that chemokines can also modulate the activities of many non-immune cells, such as endothelial cells, fibroblast, adipocytes, and tumor cells, among others, by binding to chemokine receptors expressed on these cells. The C-C Motif Chemokine Ligand 2 (CCL2, also known as monocyte chemoattractant protein-1, MCP-1) and its main receptor CCR2, a G protein-coupled receptor, have been receiving particular interest for their involvement in the pathogenesis of many diseases, including neurological diseases, atherosclerosis, obesity, diabetes, and various types of cancer. However, the intracellular mediators of CCL2-CCR2 signaling are largely unknown. Moreover, although blocking CCL2- CCR2 axis was found to be effective in several preclinical disease models, clinical trial studies of these inhibitors have shown a lack of effect, likely due to developed compensation by other chemokines and/or chemokine receptors for the loss of function of CCL2-CCR2 axis. However, the compensatory chemokines/ chemokine receptors for CCL2-CCR2 axis have been poorly defined. It is our goal for next five years to elucidate the intracellular mediators of CCL2-CCR2 signaling as well as the compensatory machinery for this axis in prostate cancer models particular under obese condition. Another area of research in my laboratory is the discovery of bioactive natural compounds. Natural compounds particularly phytochemicals are a major source for developing non-toxic preventive/therapeutic agents. Phytochemicals typically target multiple dysregulated signaling pathways involved in the development of polygenic diseases such as cancer, obesity and diabetes, therefore they may be able to provide a durable control of these diseases. However, the low bioavailability of most phytochemicals limits their efficacy in humans, and their effective doses as observed in vitro can barely be achieved in vivo. Discovery of highly effective phytochemicals with favorable bioavailability is therefore an urgent task of global priority in disease control. In our preliminary study we have identified that arctigenin, a novel anti-inflammatory lignan mainly from the herb Arctium lappa, was a potent inhibitor of various types of cancer cells with a potentially favorable bioavailability. Arctigenin has also shown to be anti - oxidant, -viral, -obesity, -diabetes, -osteoporosis, -cardiovascular diseases, -neurological diseases, and immune modulatory. Our next five years’ goal in this line of research is to fully characterize arctigenin in terms of its direct and indirect molecular targets, pharmacokinetics, and its potential influence on drug-metabolizing enzymes. The overall vision of my research program is to provide essential scientific knowledge and agents to improve the prevention and treatment of certain chronic disease including obesity and cancer, and to improve the quality of life of patients and their families.

项目概要/摘要 趋化因子是一个小细胞因子家族，以其引导细胞定向迁移的能力而闻名 表达相应的趋化因子受体。除了招募白细胞用于 炎症反应，新的证据表明趋化因子也可以调节炎症反应的活性 许多非免疫细胞，例如内皮细胞、成纤维细胞、脂肪细胞和肿瘤细胞等， 与这些细胞上表达的趋化因子受体结合。 C-C 基序趋化因子配体 2（CCL2，也 称为单核细胞趋化蛋白-1 (MCP-1) 及其主要受体 CCR2（一种 G 蛋白偶联） 受体，因其参与许多疾病的发病机制而受到特别关注， 包括神经系统疾病、动脉粥样硬化、肥胖、糖尿病和各种癌症。然而， CCL2-CCR2 信号传导的细胞内介质很大程度上未知。此外，虽然阻断了CCL2- CCR2 轴被发现在多种临床前疾病模型中有效，这些模型的临床试验研究 抑制剂表现出缺乏效果，可能是由于其他趋化因子和/或的补偿作用所致 CCL2-CCR2 轴功能丧失的趋化因子受体。然而，补偿性趋化因子/ CCL2-CCR2 轴的趋化因子受体尚未明确定义。我们未来五年的目标是 阐明 CCL2-CCR2 信号传导的细胞内介质及其补偿机制 前列腺癌模型中的轴，特别是在肥胖条件下。我实验室的另一个研究领域是 生物活性天然化合物的发现。天然化合物尤其是植物化学物质是主要的 开发无毒预防/治疗剂的来源。植物化学物质通常针对多种 信号通路失调参与癌症、肥胖等多基因疾病的发生 和糖尿病，因此它们可能能够持久控制这些疾病。然而，低 大多数植物化学物质的生物利用度限制了它们对人类的功效，以及在 体外几乎无法在体内实现。发现具有良好生物利用度的高效植物化学物质 因此，这是全球疾病控制的一项紧迫任务。在我们的初步研究中，我们已经确定 牛蒡甙元是一种新型抗炎木脂素，主要来自牛蒡草，是一种有效的抑制剂 具有潜在良好生物利用度的各种类型的癌细胞。牛蒡甙元也被证明具有抗- 氧化剂、-病毒、-肥胖、-糖尿病、-骨质疏松症、-心血管疾病、-神经系统疾病，以及 免疫调节。我们在这方面研究的未来五年目标是充分表征牛蒡甙元 其直接和间接分子靶标、药代动力学及其对药物代谢的潜在影响 酶。我的研究计划的总体愿景是提供必要的科学知识和代理 改善肥胖和癌症等某些慢性疾病的预防和治疗，并改善 患者及其家人的生活质量。