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Signaling mediators of CCL2/CCR2 and natural product discovery

CCL2/CCR2 信号传导介质和天然产物发现

基本信息

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
项目类别：
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

项目摘要

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/文摘