Biochemical Modulation of Nociceptive Circuits

伤害感受回路的生化调节

基本信息

批准号：
7347513
负责人：
Mark J. Zylka
金额：
$ 31.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347513
关键词：
Acid Phosphatase Afferent Neurons Agonist Analgesics Animal Model Antibodies Behavior Behavioral Biochemical Biological Assay Calcium Caliber Cell Line Cells Chronic Clinical Culture Media Data Disease Fluorides Genes Green Fluorescent Proteins Health Human Hyperalgesia Image Immunohistochemistry In Vitro Knockout Mice Localized Luciferases Lysophosphatidic Acid Receptors Lysophospholipids Malignant neoplasm of prostate Measures Modeling Mus Neurons Nociception Pain Pathology Peripheral Peripheral Nervous System Pharmaceutical Preparations Phosphoric Monoester Hydrolases Prostate Protein Isoforms Proteins Receptor Activation Receptor Signaling Reporter Genes Research Resistance Rodent Rodent Model Role Signal Transduction Spinal Cord Spinal Ganglia Stimulus Study Section Symptoms Techniques Testing Thinking Tissues Trigeminal System allodynia base chronic pain extracellular gabapentin human disease in vivo loss of function lysophosphatidic acid painful neuropathy prevent prostatic fraction Acid phosphatase isoenzyme research study tumor progression

项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain is a chronic and debilitating disease that is difficult to treat with existing analgesics. Recent studies reveal a critical role for lysophosphatidic acid (LPA) receptor activation in causing neuropathic pain. We found that many small diameter, presumably nociceptive, dorsal root ganglia (DRG) and trigeminal neurons express a transmembrane-localized phosphatase that dephosphorylates LPA. Based on these observations, our long term research objectives are to demonstrate that this phosphatase modulates LPA receptor signaling in vitro, using cultured sensory neurons, and in vivo, using mouse neuropathic pain models. To accomplish this, we will first use immunohistochemistry to characterize the sensory neurons that express this phosphatase and identify the peripheral tissues that are innervated by phosphatase-containing afferents. Next, we will test the hypothesis that this phosphatase modulates LPA receptor signaling in cell lines and in dissociated mouse DRG neurons using calcium imaging and luciferase reporter gene assays. We will use genetically modified mice expressing Green Fluorescent Protein to identify the DRG neurons that express this phosphatase. Finally, we will test the hypothesis that this phosphatase modulates neuropathic pain behaviors in wild-type and phosphatase knockout mice.

描述（由申请人提供）：神经性疼痛是一种慢性且使人衰弱的疾病，很难用现有的镇痛药治疗。最近的研究揭示了溶血磷脂酸 (LPA) 受体激活在引起神经性疼痛中的关键作用。我们发现许多直径较小、可能具有伤害性的背根神经节 (DRG) 和三叉神经元表达一种跨膜定位的磷酸酶，可使 LPA 去磷酸化。基于这些观察，我们的长期研究目标是证明这种磷酸酶在体外（使用培养的感觉神经元）和体内（使用小鼠神经性疼痛模型）调节 LPA 受体信号传导。为了实现这一目标，我们将首先使用免疫组织化学来表征表达这种磷酸酶的感觉神经元，并识别由含有磷酸酶的传入神经支配的外周组织。接下来，我们将使用钙成像和荧光素酶报告基因检测来测试这种磷酸酶调节细胞系和分离的小鼠 DRG 神经元中的 LPA 受体信号传导的假设。我们将使用表达绿色荧光蛋白的转基因小鼠来识别表达这种磷酸酶的 DRG 神经元。最后，我们将测试这种磷酸酶调节野生型和磷酸酶敲除小鼠的神经性疼痛行为的假设。