Genetics and phenomics of widespread neuropathic trigeminal pain in the mouse

小鼠广泛神经性三叉神经痛的遗传学和表型组学

• 批准号: 7903224
• 负责人: Ze 'ev Y. Seltzer
• 金额: $ 26.11万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903224
• 关键词: A/J Mouse; Acute; Adverse effects; Affect; Analgesics; Animal Model; Area; Astrocytes; Behavior; Behavioral; Body part; Candidate Disease Gene; Chromosome Mapping; Collection; Complex Genetic Trait; DNA; Development; Ear; Female; Future; Gated Ion Channel; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genotype; Haplotypes; Human; Hyperalgesia; Inbred Strain; Inbred Strains Mice; Individual Differences; Injury; Ion Channel; Ions; Label; Lead; Ligands; Light; Mammals; Maps; Mediating; Medical; Messenger RNA; Methods; Microglia; Modeling; Mouse Strains; Mus; Names; Nerve; Neuronal Plasticity; Neurons; Neuropathy; Pain; Patients; Pattern; Persistent pain; Phenotype; Predisposition; Quantitative Trait Loci; Recombinants; Research; Research Personnel; Sampling; Screening procedure; Seizures; Sensory; Site; Spinal; Stimulus; Symptoms; Syndrome; Tail; Testing; Tissue-Specific Gene Expression; Touch sensation; Trigeminal Neuralgia; Trigeminal System; Woman; Work; allodynia; base; chronic pain; cohort; craniofacial; excitotoxicity; genetic analysis; genetic linkage analysis; injured; male; mouse model; nerve injury; new therapeutic target; novel; orofacial; painful neuropathy; phenomics; progenitor; response; sex; spontaneous pain; tool; trait; voltage

DESCRIPTION (provided by applicant): To test the hypo,thasis.that trigeminal pain spdrom,es are complex genetic traits, we recently produced a new mouse model of kraniofacial neuropathic pain (CNP), by unilaterally cutting the infraorbital nerve (IONX). We found thaf pain to light touch (i.e., allodynia) and increased pain to noxious stimuli (i.e., hyperalgesia) appeared in both ears, paws and tail, and depended on the sex and the genetic background of the studied strains. This model is a robust platform to study genetic mechanisms underlying CNP that is seen frequently in humans, especially women. Our specific aims are to identify candidate genetic factors that contribute to differences in susceptibility to CNP. Since, some of these likely encode voltage- and ligandgated ion channel genes, in AIM-1 we will identify SNPs in 235 such genes across 20 inbred mouse strains and reconstruct their haplotypes. AIM-2: Phenotyping CNP post-IONX in these mice and a computational genetic analysis of their haplotype map, we will identify genetic factors controlling CNP. Phenoirping 23 AXB-BXA recombinant inbred mouse strains, followed by linkage analysis of their known genetic map will enable us to idenbfy QTL intervals for CNP. Using expression arrays we will identify genes differentially expressed in trigeminal subnucleus caudalis (Vc) of strains contrasting on CNP levels post-IONX. Superposition of these 3 maps should enable candidate genes for CNP to be identified. Not part of this study, we will genotype these genes in cohorts of trigeminal (and other) neuropathic pain patients. AIM-3: CNP levels in 43 strains typed in AIM 2 will enable us to offer the highest contrasting strains as a standardized new platform to study mechanisms of CNS plasticity after nerve injury, test novel analgesics and produce new hypotheses for indepth future studies. We will phenotype 8 of these strains for traits supposedly correlating CNP and undetlying central plasticity following nerve injury: (i) excitotoxic destruction of pain-suppressing neurons in Vc, (ii) Seizure proneness as a probe of CNS inhibitions, (iii) changes in astro- and microglial cells, and (iv) FOS labeling to study plasticity in somatotic maps of Vc and lumbosacral neuronal pools that respond to acute noxious stimulation in sites of extratenitorial hyperalgesia. These genetic and phenomic studies are proposed as a new and robust model to study trigeminal pain syndromes. Identification of genetic factors affecting trigeminal pain syndromes could provide novel therapeutic targets.

描述(申请人提供)：为了测试三叉神经痛综合征、ES是复杂的遗传特征，我们最近制作了一种新的颅面神经病理性疼痛(CNP)小鼠模型，方法是切断一侧眶下神经(Ion X)。我们发现，对轻度接触的疼痛(即超敏)和对伤害性刺激的增加的疼痛(即痛敏)出现在耳朵、爪子和尾巴上，并取决于所研究品系的性别和遗传背景。这个模型是一个强大的平台来研究CNP的遗传机制，CNP在人类，特别是女性中经常出现。我们的具体目标是确定导致CNP易感性差异的候选遗传因素。由于其中一些可能编码电压和配体门控离子通道基因，在AIM-1中，我们将在20个近交系小鼠品系的235个这样的基因中识别SNPs，并重建它们的单倍型。目的-2：对这些小鼠的CNP进行表型分型，并对其单倍型图谱进行计算遗传学分析，以确定控制CNP的遗传因素。对23个AXB-BXA重组近交系小鼠品系进行遗传连锁分析，将使我们能够确定CNP的QTL区间。利用表达芯片，我们将发现在三叉神经尾侧亚核(VC)差异表达的基因，这些基因在离子X后的CNP水平上存在差异。这3个图谱的叠加应能识别CNP的候选基因。不是这项研究的一部分，我们将在三叉神经痛(和其他)神经性疼痛患者的队列中对这些基因进行基因分型。目的-3：AIM-2分型的43株菌株的CNP水平将使我们能够提供最高对比度的菌株作为标准化的新平台，以研究神经损伤后中枢神经系统可塑性的机制，测试新的止痛药，并为未来的深入研究提出新的假设。我们将这些菌株的8型表型与神经损伤后明显的中枢可塑性联系起来：(I)Vc内疼痛抑制神经元的兴奋性毒性破坏，(Ii)作为CNS抑制的探针的癫痫倾向，(Iii)星形胶质细胞和小胶质细胞的变化，以及(Iv)FOS标记研究Vc和腰椎神经元池对幕外伤害性刺激部位的急性伤害性刺激做出反应的躯体图谱的可塑性。这些遗传学和表现学研究被认为是研究三叉神经痛综合征的一种新的、可靠的模型。识别影响三叉神经痛综合征的遗传因素可提供新的治疗靶点。