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.

项目摘要/摘要 趋化因子是一个小细胞因子家族，以指导细胞的定向迁移而闻名 表达相应的趋化因子接收器。除了他们在招募白细胞的活动外 炎症反应，新兴的证据表明，趋化因子还可以调节 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 与在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，也是 被称为单核细胞化学吸引蛋白-1，MCP-1）及其主体CCR2，G蛋白偶联 接收者，由于其参与许多疾病的发病机理，已经获得了特别的利益， 包括神经疾病，动脉粥样硬化，肥胖，糖尿病和各种类型的癌症。但是， CCL2-CCR2信号传导的细胞内介体在很大程度上未知。而且，尽管阻止了CCL2- 发现CCR2轴在几种临床前疾病模型中有效， 抑制剂显示出缺乏作用，这可能是由于其他趋化因子和/或 CCL2-CCR2轴功能丧失的趋化因子受体。但是，代偿性趋化因子/ CCL2-CCR2轴的趋化因子受体的定义很差。接下来的五年我们的目标是 阐明CCL2-CCR2信号传导的细胞内介质以及此的补偿机制 前列腺癌模型的轴在肥胖状态下。我实验室的另一个研究领域是 发现生物活性天然化合物。天然化合物特别是植物化学物质是主要的 开发无毒预防/治疗剂的来源。植物化学物质通常靶向多个 涉及多基因疾病（例如癌症）肥胖的多基因疾病发展的信号通路失调 和糖尿病，因此它们可能能够对这些疾病提供持久的控制。但是，低 大多数植物化学物质的生物利用度限制了其在人类中的有效性，并且在 体内几乎无法实现体内。发现具有良好生物利用度的高效植物化学物质 因此，这是全球疾病控制优先事项的紧迫任务。在我们的初步研究中，我们已经确定 阿氏霉素是一种新型的抗炎木质，主要来自草药北心，是一种潜在的抑制剂 各种类型的癌细胞具有潜在的生物利用度。阿氏霉素也已显示为抗 - 氧化剂， - 病毒， - 肥胖， - 糖尿病， - 骨质疏松症， - 心脏血管疾病， - 神经疾病和 - 神经疾病和 免疫调节。我们在这一研究中的未来五年目标是用术语充分表征亚氏素蛋白 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。我的研究计划的整体愿景是为基本科学知识和代理提供给 改善某些慢性疾病在内的预防和治疗，包括肥胖和癌症，并改善 患者及其家人的生活质量。