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(申请人提供)：需要治疗慢性疼痛的新方法，特别是因为现有的止痛药有严重的副作用，在治疗炎症性疼痛和神经病理性疼痛方面并不总是有效，这是人类最常见的两种慢性疼痛形式。炎症和神经损伤导致一种复杂的化学混合物的释放，这些化学物质通过分子上不同的伤害性(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敏感性 神经节(DRG)和三叉神经节神经元。不幸的是，阻断个体伤害性感受器的努力到目前为止还没有产生治疗慢性疼痛的有效方法。在这里，我们提出了一种创新的方法来降低疼痛过敏症，绕过了这个与受体多样性相关的长期问题。我们的方法是基于选择性地降低DRG神经元中脂质第二信使磷脂酰肌醇4，5-二磷酸(PIP2)的水平。大多数伤害性感受器需要PIP2来启动下游信号。此外，许多检测伤害性刺激的色氨酸通道和调节膜兴奋性的离子通道都需要PIP2来激活。因此，PIP2处于促进和维持慢性疼痛的不同受体、离子通道和信号通路的关键汇聚点。在对小鼠的初步研究中，我们发现了一种在DRG神经元中产生至少50%PIP2的脂蛋白激酶。此外，这种脂激酶的失活大大减少了对炎性介质的伤害敏感化。根据我们的初步数据，我们假设这种脂激酶通过PIP2依赖的机制来调节DRG神经元中的伤害性前受体信号和体内的痛敏化。为了验证这一假设，我们将：1.使用急性、慢性和自发性疼痛的小鼠模型，包括炎症性疼痛和神经病理性疼痛的模型，评估这种脂激酶在体内调节伤害性敏感化的程度。我们将使用一种创新的遗传方法来降低激酶的活性。这种方法选择性地降低了DRG中PIP2的浓度，但不影响处理疼痛信号的其他组织中的PIP2浓度。我们将通过生化救援实验进一步评估PIP2的依赖性。2.评估该激酶通过不同的伤害性感受器调节信号的程度，包括G蛋白偶联受体、酪氨酸激酶受体和检测伤害性刺激的Trp通道。3.利用一种新的条件性基因敲除小鼠，仅在成人感觉神经元中诱导性地删除该激酶，并评估该激酶在多大程度上调节炎症性疼痛和神经病理性疼痛的启动和维持。我们将是第一个严格研究这种激酶在慢性疼痛中的重要性的人。我们的初步数据表明，这种脂激酶是疼痛信号和敏化的主要调节器。

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