Cannabidiol and immunosuppression: Mechanism of induction and role of MDSCs

大麻二酚和免疫抑制：MDSC 的诱导机制和作用

基本信息

批准号：
8635788
负责人：
Venkatesh L Hegde
金额：
$ 16.4万
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：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635788
关键词：
Accident and Emergency department Adenosine A2A Receptor Adverse effects Affinity Age Apoptosis Applications Grants Area Awareness Behavioral Binding Biological Bone Marrow Brain CD8-Positive T-Lymphocytes CNR1 gene CNR2 gene CSF3 gene Cannabidiol Cannabinoids Cannabis Cannabis sativa plant Cells Chronic Complex Cytotoxic T-Lymphocytes Data Doctor of Philosophy Down-Regulation Drug abuse Drug usage Drug user Emotional Enzymes Epigenetic Process Exposure to Female Goals Health Human ITGAM gene Illicit Drugs Immune Immune System Diseases Immune response Immune system Immunosuppression Immunosuppressive Agents Infection Inflammatory Lead Malignant Neoplasms Marijuana Mediating Mediator of activation protein Mentored Research Scientist Development Award Mentors Metabolism Methodology MicroRNAs Modeling Molecular Mus Myelogenous Natural Killer Cells Nature Neoplasm Metastasis PPAR gamma Pathway interactions Patients Peritoneum Peroxisome Proliferator-Activated Receptors Pharmacodynamics Phenotype Play Process Property Public Health Regulation Regulatory Pathway Research Research Personnel Resistance Risk Role Route Source South Carolina Suppressor-Effector T-Lymphocytes Surveys T cell response Testing Tetrahydrocannabinol Time Tissues Training Transfection Tumor Immunity United States Universities Vanilloid Visit Wild Type Mouse arginase cannabinoid receptor career career development chemokine cytokine drug abuse prevention fighting immune function improved in vivo in vivo Model intraperitoneal knowledge base mast cell medical schools overexpression professor psychologic receptor research study response sedative transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): This is an application for the mentored research Career Development K01 award for Venkatesh Hegde (PhD), a Research Assistant Professor at the University of South Carolina. Dr. Hegde plans to reorient his research efforts and develop his career in the area of prevention of Drug Abuse with the major goal to understand the effects of marijuana components on the immune system by precisely elucidating mechanisms. The candidate seeks three years of protected time and support to obtain advanced training in new fields of research, and towards career development activities necessary to become an independent investigator. Cannabis or marijuana is the most widely consumed illicit drug in United States and its abuse is a major public health issue. In addition to behavioral, psychological and emotional adverse effects, cannabinoid compounds present in marijuana can cause significant immune-altering effects. Dr. Hegde's exciting preliminary results point to a new mechanism of immune-dysfunction caused by cannabinoids, involving robust induction of myeloid-derived suppressor cells (MDSC) in vivo via specific receptor-mediated mechanisms. These potent suppressor cells are known to dampen the immune system's capacity to fight tumors and infections. The central hypothesis of the proposed research is that induction of functional MDSC and its associated molecular networks by cannabidiol (CBD) is an important mechanism of immunosuppression with major biological significance. In Aim 1, Dr. Hegde will investigate the role of microRNA-mediated regulatory pathways involved in the induction of functionally active MDSC by CBD from bone marrow precursors. He will specifically study the mechanism of down-regulation and role of miRNA-706 and miRNA-455 in the regulation of their target transcription factors Stat1 and Stat6, and in-turn, Arginase 1 and iNos enzymes critical for the immunosuppressive function of MDSC. In Aim 2, he will investigate its impact on tumor progression and anti-tumor immune response in vivo using CBD-sensitive and CBD-resistant tumor models. With an accomplished mentoring team lead by Dr. Mitzi Nagarkatti, Professor and Chair at the USC School of Medicine, with the new cutting-edge facilities for epigenetics/ miRNA research, Dr. Hegde will carry out these experiments while obtaining intensive training in several advanced methodologies and will undergo overall career development including training in grantsmanship. With this K01 award, the candidate will establish a strong knowledgebase and expertise, generate sufficient pilot data, and develop a competent R01 level grant application to successfully launch his independent research career in this unique line of research.

描述（由申请人提供）：这是南卡罗来纳大学的研究助理教授Venkatesh Hegde（PhD）的指导研究职业发展K01奖的申请。 Hegde博士计划重新定位他的研究工作，并在预防药物滥用领域发展其职业生涯，其主要目标是通过精确阐明机制来了解大麻成分对免疫系统的影响。候选人寻求三年的受保护时间和支持，以在新的研究领域获得高级培训，并为成为独立研究者所必需的职业发展活动。大麻或大麻是美国最广泛消耗的非法药物，其滥用是一个主要的公共卫生问题。除了行为，心理和情绪不利影响外，大麻中存在的大麻素化合物还会引起明显的免疫改变作用。 Hegde博士令人兴奋的初步结果表明，由大麻素引起的免疫功能的新机制，涉及通过特定受体介导的机制在体内强烈诱导粒细胞来源的抑制细胞（MDSC）。已知这些有效的抑制细胞会抑制免疫系统抵抗肿瘤和感染的能力。拟议研究的中心假设是，大麻二醇（CBD）诱导功能性MDSC及其相关的分子网络是免疫抑制的重要机制，具有重要的生物学意义。在AIM 1中，Hegde博士将研究MicroRNA介导的调节途径在骨髓前体中通过CBD诱导功能活性MDSC的作用。他将专门研究miRNA-706和miRNA-455在调节其目标转录因子STAT1和STAT6的调节中的下调和作用的机制，以及在旋转，精氨酸酶1和iNOS酶中至关重要的 MDSC的免疫抑制功能。在AIM 2中，他将使用CBD敏感和抗CBD耐药性肿瘤模型研究其对体内肿瘤进展和抗肿瘤免疫反应的影响。由USC医学院教授兼主席Mitzi Nagarkatti博士领导的很有成就的团队，以及新的表观遗传学/ MIRNA研究的新尖端设施，Hegde博士将在几种先进的方法中进行深入培训，并将在多种先进的方法中进行深入的培训，并将接受包括在助理学的整体培训中进行整体职业发展。通过这项K01奖，候选人将建立强大的知识基础和专业知识，生成足够的试点数据，并开发有能力的R01级赠款应用程序，以成功地在这一独特的研究系列中启动他的独立研究生涯。