Project 4

项目4

基本信息

批准号：
7612980
负责人：
RAPHAEL MECHOULAM
金额：
$ 13.1万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612980
关键词：
Ablation Age Agonist Allosteric Site Amides Amino Acids Anabolism Animal Model Animals Antibodies Astrocytes Axon Behavior Binding Biological Biological Assay Biological Models Blood - brain barrier anatomy Bone Resorption Bone remodeling Brain Brain Injuries CNR1 gene Cannabinoids Cell Proliferation Cells Characteristics Chinese Hamster Ovary Cell Collaborations Collagen Complement Craniocerebral Trauma Cyclic AMP Data Degenerative Disorder Dissociation Drug Addiction Drug Delivery Systems Embryo Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Equilibrium Esters Evaluation Exhibits Family suidae Fatty Acids Funding Genes Glycerol Hand Healed High Pressure Liquid Chromatography Hippocampus (Brain)Human Immigration Immunoblotting In Vitro Injury Interneurons Knock-out Knockout Mice Laboratories Ligands Mails Maps Mass Fragmentography Measures Mediating Mediator of activation protein Membrane Metabolic Metabolism Methods Modeling Molecular Morbidity - disease rate Muramidase Mus Natural regeneration Nerve Neuraxis Neurodegenerative Disorders Neurologic Neurons Neuroprotective Agents Oligodendroglia Osteoblasts Osteocalcin Osteoclasts Osteogenesis Osteoporosis Pain Patients Peripheral Phenotype Physiological Physiological Processes Population Process Production Property Prosencephalon Receptor Activation Recovery Regulation Reporting Reverse Transcriptase Polymerase Chain Reaction Rewards Role Screening procedure Serine Severities Site Skeleton Societies System TRPV1 gene Testing Time Tissues Tracer Trauma Traumatic Brain Injury Tyrosine 3-Monooxygenase Vas deferens structure X-Ray Computed Tomography anandamide base bone bone cell bone mass bone metabolism cannabinoid receptor capsaicin receptor computerized functional disability healing in vitro activity in vivo injured mouse model nerve stem cell nestin protein neurogenesis novel prevent professor promoter receptor response response to injury sex skeletal

项目摘要

Our main accomplishments during the previous funding cycle relevant to the present application are: 1. Identification of new endocannabinoid (EC)-like compounds in the central nervous system, their synthesis and evaluation in various biological settings; 2. Characterization of a neuroprotective role for the EC system in traumatic brain injury (TBI). 3. Defining a role for the EC system in the regulation of skeletal metabolism. Based on our findings we hypothesize that the ECs, EC-like compounds and the cannabinoid receptors have differential and distinct pathophysiologic roles, both after TBI and in maintaining bone remodeling at balance. We propose to test this hypothesis using an array of newly synthesized EC-like compounds (i.e., fatty acid ethanolamides, fatty acid glyceryl esters and fatty acid amides), test their binding to cannabinoid receptors and define their pharmacological actions (by Dr. Mechoulam). This will be followed by identification of corresponding endogenous materials in the brain (by Dr. Mechoulam) and testing their effects in a mouse model for TBI and their role in neurogenesis (by Dr. Shohami) and on the skeleton (by Dr. Bab). These compounds will be also assessed in other biological models available to the PPG such as Dr. Martin's models for pain and reward (Project 1). To further map the role of EC system components in post-TBI recovery and bone remodeling we will analyze TBI-triggered processes (Dr. Shohami) and bone metabolism (Dr. Bab) in mice with conditional deletion of EC genes in the brain and in the skeleton. Some of these mice will be generated by Dr. Cravatt (Project 3) or provided by our collaborators Dr. Zimmer and Dr. Lutz. In a complementary strategy, we will test the post-TBI and skeletal effects of inhibitors of enzymes involved in EC synthesis and degradation (from Drs. Razdan and Cravatt) and of cannabinoid receptor agonists and antagonists (from Drs. Razdan and Mechoulam). Mapping the activity of the EC-like compounds and each of the EC system components is proposed with the objective of identifying molecular drug targets for the benefit of TBI victims, patients with neurodegenerative diseases and sufferers of skeletal deficits resulting from trauma and osteoporosis. Such mapping will probably contribute to the general understanding of the EC system and hence, drug dependence.

我们在上一个与本申请有关的资金周期中的主要成就是：1。鉴定中枢神经系统中新的内源性大麻素（EC）样化合物，它们在各种生物环境中的合成和评估； 2。表征神经保护作用脑外伤（TBI）中的EC系统。 3。定义EC系统在调节中的作用骨骼代谢。根据我们的发现，我们假设EC，类似EC的化合物和大麻素受体在TBI和IN之后具有鉴别和不同的病理生理作用保持骨头重塑平衡。我们建议使用新数组来检验该假设合成的EC状化合物（即脂肪酸乙醇酰胺，脂肪酸甘油酯和脂肪酸酰胺），测试它们与大麻素受体的结合并定义其药理作用（博士 Mechoulam）。随后将鉴定大脑中相应的内源性材料（由Mechoulam博士）并测试其在小鼠模型中的效果及其在神经发生中的作用（通过 Shohami博士）和骨骼（由Bab博士）。这些化合物也将在其他 PPG可用的生物模型，例如Martin博士的疼痛和奖励模型（项目1）。到进一步绘制EC系统组件在TBI恢复和骨骼重塑中的作用，我们将分析有条件的小鼠中的TBI触发过程（Shohami博士）和骨代谢（BAB）删除大脑和骨骼中的EC基因。这些小鼠中的一些将由博士生成。 Cravatt（项目3）或我们的合作者Zimmer博士和Lutz博士提供。在补充中策略，我们将测试参与EC合成的酶抑制剂的TBI后和骨骼作用和退化（来自Razdan博士和Cravatt博士）以及大麻素受体激动剂和拮抗剂（来自Razdan博士和Mechoulam）。映射类似EC的化合物和EC的活性提出了系统组件，目的是识别分子药物靶标的，以获取 TBI受害者，神经退行性疾病的患者以及由创伤和骨质疏松症。这样的映射可能会有助于对EC的一般理解系统，因此，药物依赖性。