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.

项目总结/摘要 趋化因子是一类小分子细胞因子，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。除了它们在募集白细胞用于 炎症反应，新出现的证据表明，趋化因子也可以调节活动， 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CCL2）是一种趋化因子配体， 称为单核细胞趋化蛋白-1，MCP-1）及其主要受体CCR 2，一种G蛋白偶联的 受体，由于它们参与许多疾病的发病机制而受到特别的关注， 包括神经疾病、动脉粥样硬化、肥胖症、糖尿病和各种类型的癌症。但 CCL2-CCR2信号传导的细胞内介质在很大程度上是未知的。此外，虽然阻断CCL2- 发现CCR2轴在几种临床前疾病模型中有效，这些临床试验研究 抑制剂显示缺乏效果，可能是由于其他趋化因子和/或 趋化因子受体CCL2-CCR2轴功能丧失。然而，代偿性趋化因子/ CCL2-CCR2轴的趋化因子受体的定义很差。我们今后五年的目标是， 阐明CCL2-CCR2信号传导的细胞内介质以及对此的补偿机制。 轴在前列腺癌模型中，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，特别是植物化学物质， 开发无毒预防/治疗剂的来源。植物化学物质通常针对多种 参与多基因疾病如癌症、肥胖症、 和糖尿病，因此它们可能能够提供对这些疾病的持久控制。然而，低 大多数植物化学物质的生物利用度限制了它们在人类中的功效，并且它们的有效剂量如在 在体内几乎无法实现。发现具有良好生物利用度的高效植物化学物质 因此是疾病控制中全球优先紧迫任务。在我们的初步研究中， 牛蒡苷元是一种主要来源于牛蒡的新型抗炎木脂素， 具有潜在有利的生物利用度的各种类型的癌细胞。牛蒡子苷元也被证明是抗- 氧化剂，-病毒，-肥胖症，-糖尿病，-骨质疏松症，-心血管疾病，-神经系统疾病，和 免疫调节我们未来五年的目标是在这方面的研究是充分表征牛蒡子苷元 其直接和间接的分子靶点，药代动力学及其对药物代谢的潜在影响 内切酶我研究项目的总体愿景是提供必要的科学知识和试剂， 改善对某些慢性疾病的预防和治疗，包括肥胖和癌症，并改善 患者及其家属的生活质量。