Lipid kinase regulation of pain signaling and sensitization

脂质激酶对疼痛信号传导和敏化的调节

• 批准号: 9279273
• 负责人: Mark J. Zylka
• 金额: $ 32.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279273
• 关键词: AVIL gene; Acute Pain; Adult; Adverse effects; Afferent Neurons; Analgesics; Behavioral; Biochemical; Bradykinin; Brain; Bypass; Chemicals; Complex; Data; Dependence; Development; Enzymes; Future; G-Protein-Coupled Receptors; Gold; Human; Hydrolysis; Hypersensitivity; Individual; Inflammation; Inflammatory; Ion Channel; Knockout Mice; Lead; Lipids; Maintenance; Medical; Membrane; Modeling; Molecular; Mus; Nerve Growth Factors; Neurons; Nociception; Opioid; Pain; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Process; Property; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research; Second Messenger Systems; Signal Pathway; Signal Transduction; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; TRP channel; Tamoxifen; Testing; Thermal Hyperalgesias; Time; Tissues; base; chronic pain; common symptom; effective therapy; experimental study; genetic approach; in vivo; inflammatory pain; inhibitor/antagonist; innovation; knock-down; lysophosphatidic acid; mechanical allodynia; mouse model; nerve injury; nociceptive response; novel; novel strategies; pain symptom; painful neuropathy; phosphatidylinositol 4-phosphate; public health relevance; receptor; reduce symptoms; response; spontaneous pain

DESCRIPTION (provided by applicant): New approaches for treating chronic pain are needed, particularly since existing analgesics have serious side effects and are not always effective at treating inflammatory pain and neuropathic pain-the two most common forms of chronic pain in humans. Inflammation and nerve injury lead to the release of a complex mix of chemicals that signal through molecularly diverse pronociceptive (pain-producing) receptors. Activation of these receptors increases the excitability and sensitivity of nociceptive dorsal root ganglia (DRG) and trigeminal ganglia neurons. Unfortunately, efforts to block individual pronociceptive receptors have so far failed to produce effective treatments for chronic pain. Here, we propose an innovative approach to reduce pain hypersensitivity that bypasses this long-standing problem associated with receptor diversity. Our approach is based on selectively reducing the level of the lipid second messenger phosphatidylinositol 4,5- bisphosphate (PIP2) in DRG neurons. Most pronociceptive receptors require PIP2 to initiate downstream signaling. Moreover, many TRP channels that detect noxious stimuli and ion channels that regulate membrane excitability require PIP2 for activity. PIP2 thus sits at a key convergence point for diverse receptors, ion channels and signaling pathways that promote and maintain chronic pain. In preliminary studies with mice, we identified a lipid kinase that generates at least 50% of all PIP2 in DRG neurons. Moreover, inactivation of this lipid kinase profoundly reduced nociceptive sensitization in response to an inflammatory agent. Based on our preliminary data, we hypothesize that this lipid kinase acts through PIP2 dependent mechanisms to regulate pronociceptive receptor signaling in DRG neurons and pain sensitization in vivo. To test this hypothesis we will: 1. Evaluate the extent to which this lipid kinase regulates nociceptive sensitization in vivo, using mouse models of acute, chronic and spontaneous pain, including models of inflammatory pain and neuropathic pain. We will use an innovative genetic approach to knock-down kinase activity. This approach selectively reduces PIP2 concentration in DRG but does not affect PIP2 concentration in other tissues that process pain signals. We will further evaluate PIP2-dependence using biochemical rescue experiments. 2. Evaluate the extent to which this kinase regulates signaling through diverse pronociceptive receptors, including G protein-coupled receptors, a tyrosine kinase receptor, and TRP channels that detect noxious stimuli. 3. Utilize a new conditional knockout mouse to inducibly delete this kinase only in sensory neurons of adults and to evaluate the extent to which this kinase regulates initiation and maintenance of inflammatory pain and neuropathic pain. We will be the first to rigorously study the importance of this kinase in the setting of chronic pain. Our preliminary data suggest this lipid kinase is a master regulator of pain signaling and sensitization.

描述（由申请人提供）：需要治疗慢性疼痛的新方法，尤其是因为现有的镇痛药具有严重的副作用，并且并不总是有效地治疗炎症性疼痛和神经性疼痛 - 这两种最常见的慢性疼痛形式是人类的慢性疼痛。炎症和神经损伤导致化学物质的复杂混合物释放，这些化学物质通过分子引起感受（产生疼痛）受体发出信号。这些受体的激活增加了伤害性背根的兴奋性和灵敏度 神经节（DRG）和三叉神经神经元。不幸的是，迄今为止，阻止单个引起感人受体的努力未能为慢性疼痛产生有效的治疗方法。在这里，我们提出了一种创新的方法来减少疼痛超敏反应，绕过与受体多样性相关的长期问题。我们的方法是基于选择性降低DRG神经元中脂质二磷脂酰肌醇4,5-双磷酸（PIP2）的水平。大多数引起摄影受体需要PIP2启动下游信号传导。此外，许多检测调节膜兴奋性有害刺激和离子通道的TRP通道都需要PIP2进行活动。因此，PIP2位于促进和维持慢性疼痛的各种受体，离子通道和信号通路的关键收敛点。在使用小鼠的初步研究中，我们确定了一种脂质激酶，该脂质激酶在DRG神经元中至少产生所有PIP2的50％。此外，这种脂质激酶的失活因响应炎症剂而严重降低了伤害感受敏化。基于我们的初步数据，我们假设该脂质激酶通过pip2依赖机制作用，以调节DRG神经元中的引起感受感受器的受体信号传导和体内疼痛敏化。为了检验该假设，我们将：1。使用急性，慢性和自发疼痛的小鼠模型，包括炎症性疼痛和神经性疼痛的模型，评估这种脂质激酶在体内调节伤害感性的程度。我们将使用创新的遗传方法来敲门激酶活性。这种方法有选择地降低DRG中的PIP2浓度，但不会影响处理疼痛信号的其他组织中的PIP2浓度。我们将使用生化救援实验进一步评估PIP2依赖性。 2。评估该激酶通过多种造影受众受体（包括G蛋白偶联受体，酪氨酸激酶受体和检测有害刺激的TRP通道）调节信号传导的程度。 3。利用一种新的条件基因敲除小鼠仅在成年人的感觉神经元中删除这种激酶，并评估这种激酶调节炎症性疼痛和神经性疼痛的起始和维持的程度。我们将是第一个严格研究这种激酶在慢性疼痛环境中的重要性的人。我们的初步数据表明，这种脂质激酶是疼痛信号传导和敏化的主要调节剂。

项目成果

Conditional deletion of Pip5k1c in sensory ganglia and effects on nociception and inflammatory sensitization.

感觉神经节中 Pip5k1c 的条件性缺失及其对伤害感受和炎症敏化的影响。

• DOI: 10.1177/1744806917737907
• 发表时间: 2017
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Loo,Lipin;Zylka,Mark
• 通讯作者: Zylka,Mark