VOLTAGE-GATED CALCIUM CHANNELS IN MIGRAINE PATHOPHYSIOLOGY

偏头痛病理生理学中的电压门控钙通道

基本信息

批准号：
9464567
负责人：
YUQING CAO
金额：
$ 33.36万
依托单位：
WASHINGTON UNIVERSITY
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：
2014-07-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9464567
关键词：
Afferent Neurons Attenuated Behavior Calcium Channel Caliber Classic Migraine Coupled Coupling Disease Dura Mater Exhibits Exposure to Familial Hemiplegic Migraine Family Functional disorder Genes Goals Grant Head Headache Healthcare Systems Homeostasis Human Imaging Techniques Incidence Individual Inflammation Mediators Ion Channel Ions Isolectin Migraine Modeling Monitor Mus Mutation National Institute of Neurological Disorders and Stroke Neurons Neurotransmitters Nociception Orofacial Pain Outcome PHluorin Paper Patients Pharmaceutical Preparations Population Potassium Channel Prevention Preventive Preventive therapy Public Health Research Signal Transduction Societies Specificity Spinal Ganglia Structure of trigeminal ganglion Symptoms Synapses Synaptic Transmission Testing Therapeutic Thinness Trigeminal System Wild Type Mouse Work channel blockers face skin insight interdisciplinary approach knock-down loss of function loss of function mutation mouse model mutant neuronal circuitry neuronal excitability neurotransmission neurovascular optical imaging overexpression presynaptic prevent prophylactic public health relevance response small hairpin RNA triptans voltage

项目摘要

DESCRIPTION (provided by applicant): Migraine is one of the most common neurovascular disorders. It is highly debilitating and difficult to treat. The disease mechanisms may involve abnormal ion homeostasis and neurotransmission. Multiple mutations in the gene encoding CaV2.1, the pore-forming subunit of human P/Q-type voltage-gated Ca2+ channel (VGCC), have been associated with familial hemiplegic migraine type 1 (FHM-1), a subclass of migraine with aura. Many of the migraine preventive and abortive drugs modulate the function of VGCCs but with poor specificity and efficacy. The overall goal of this project is to better understand th contribution of individual VGCC subtypes to the pathophysiology of migraine headache. In addition, the potential of VGCC blockers as anti-migraine therapeutics will be directly tested. Recent studies from our lab have found that loss-of-function (LOF) CaV2.1 mutations cause a decrease of P/Q- type current and a compensatory increase in N-type VGCC current in all subtypes of trigeminal ganglion (TG) and dorsal root ganglion neurons. Interestingly, a selective increase in LVA T-type VGCC current occurs only in small-diameter TG neurons that do not bind to isolectin B4 (IB4-). Moreover, LOF CaV2.1 mutations results in hyper-excitability of small IB4- neurons innervating the dura but not the facial skin. This is consistent with the fact that, other than migraine headache, FHM-1 patients do not show higher incidence of other somatic or orofacial pain. Importantly, pretreatment of wild-type mice with T- or N-type VGCC blockers significantly reduced the duration of head-directed nocifensive behavior in a mouse model of headache, indicating that VGCCs are involved in the activation of the neuronal circuit underlying migraine headache. In this project we propose to employ a multidisciplinary approach to investigate the mechanisms through which multiple VGCCs regulate the excitability and synaptic transmission of dural afferent neurons, thereby modulating the gain of the migraine circuit. First, we will test the hypothesis that P/Q-type Ca2+ channels regulate the excitability o small IB4- dural afferent neurons via functional coupling of the Ca2+-activated TRESK background K+ channels. We will investigate whether enhancing TRESK channel activity can reverse the hyper-excitability of dural afferent neurons and inhibit headache-like behavior in a mouse model. Secondly, we will use optical imaging technique to elucidate the contribution of N-type and other subtypes of VGCCs to Ca2+ influx synaptic transmission at dural afferent terminals. Finally, we will use a mouse model of headache to test the hypothesis that N- and T-type VGCCs in dural afferent neurons are potential targets for anti-migraine therapeutics. We will test whether N- and T-type blockers can be used for both abortive and preventive therapy of migraine headache. Taken together, the outcome of this project will offer new insights into the contribution of VGCCs to migraine pathophysiology as well as the therapeutic potential of trigeminal VGCCs and their downstream effector(s) in migraine treatment and prevention.

描述（由申请人提供）：偏头痛是最常见的神经血管疾病之一。这是高度衰弱的，难以治疗。疾病机制可能涉及异常的离子稳态和神经传递。编码CAV2.1的多个突变，人类P/Q型电压门控CA2+通道（VGCC）的孔形成亚基与家族性偏瘫偏头痛1型（FHM-1），偏头痛的偏头痛偏头痛（FHM-1）有关。许多偏头痛预防和流产药物调节VGCC的功能，但特异性和功效差。该项目的总体目标是更好地了解单个VGCC亚型对偏头痛的病理生理学的贡献。此外，将直接测试VGCC阻滞剂作为抗毛因治疗剂的潜力。我们实验室的最新研究发现，功能丧失（LOF）CAV2.1突变导致P/Q-类型电流减少，并且在所有亚型三叉神经节（TG）和背根神经神经元中，N型VGCC电流的补偿性增加。有趣的是，LVA T型VGCC电流的选择性增加仅在不结合分离蛋白B4（IB4-）的小直径TG神经元中发生。此外，LOF CAV2.1突变导致小型IB4神经元的高度启发性，而不是面部皮肤。这与以下事实是一致的：除了偏头痛之外，FHM-1患者没有显示出其他体细胞或口罩疼痛的发病率更高。重要的是，用T-或N型VGCC阻滞剂对野生型小鼠进行预处理可显着降低头痛的小鼠头痛模型中头指导的鼻型行为的持续时间，这表明VGCC参与了偏头痛的神经元电路的激活。在这个项目中，我们建议采用一种多学科方法来研究多个VGCC调节硬膜传入神经元的兴奋性和突触传播的机制，从而调节偏头痛电路的增益。首先，我们将检验以下假设：P/Q-Type Ca2+通道通过CA2+激活的TRESK背景K+通道的功能耦合来调节小型IB4-IB4-Dural传入神经元的兴奋性。我们将调查增强TRESK通道活性是否可以逆转硬膜传入神经元的高兴趣性并抑制小鼠模型中的头痛行为。其次，我们将使用光学成像技术来阐明VGCC的N型和其他亚型对Dural Acterrent端子上Ca2+涌入突触传播的贡献。最后，我们将使用头痛的小鼠模型来检验假说中的N-和T型VGCC的假设，这是硬膜传入神经元中的N-和T型VGCC是抗毛因治疗剂的潜在靶标。我们将测试N-和T型阻滞剂是否可以用于偏头痛的流产和预防性治疗。综上所述，该项目的结果将为VGCC对偏头痛病理生理学的贡献以及三叉神经VGCC的治疗潜力及其下游效应子（S）在偏头痛治疗和预防方面的治疗潜力提供新的见解。