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: 7488577
• 负责人: Ze 'ev Y. Seltzer
• 金额: $ 26.6万
• 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/7488577
• 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; Copy Number Polymorphism; DNA; Depth; 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; novel; novel therapeutics; orofacial; painful neuropathy; progenitor; response; sex; spontaneous pain; therapeutic target; 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（由申请人提供）：为了测试三叉神经疼痛综合征是复杂遗传特征的假设，我们最近通过单侧切断眶下神经（IONX）制作了一种新的颅面神经性疼痛（CNP）小鼠模型。我们发现，双耳、爪子和尾巴均出现轻触疼痛（即异常性疼痛）和有害刺激疼痛加剧（即痛觉过敏），这取决于所研究品系的性别和遗传背景。该模型是研究人类（尤其是女性）中常见的 CNP 潜在遗传机制的强大平台。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离子通道基因，因此在 AIM-1 中，我们将在 20 个近交小鼠品系的 235 个此类基因中识别 SNP，并重建它们的单倍型。 AIM-2：对这些小鼠进行 IONX 后的 CNP 表型分析并对其单倍型图进行计算遗传分析，我们将确定控制 CNP 的遗传因素。 Phenoirping 23 AXB-BXA 重组近交小鼠品系，然后对其已知遗传图谱进行连锁分析，将使我们能够确定 CNP 的 QTL 区间。使用表达阵列，我们将鉴定在 IONX 后 CNP 水平对比的菌株三叉神经尾亚核 (Vc) 中差异表达的基因。这 3 个图谱的叠加应该能够识别出 CNP 的候选基因。这不是本研究的一部分，我们将在三叉神经（和其他）神经性疼痛患者群体中对这些基因进行基因分型。 AIM-3：AIM 2 中分型的 43 种菌株的 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来研究神经损伤后中枢神经系统可塑性的机制，测试新型镇痛药并为未来的深入研究提出新的假设。我们将对这些菌株中的 8 种进行表型分析，以了解据称与 CNP 和神经损伤后中枢可塑性相关的特征：(i) Vc 中疼痛抑制神经元的兴奋性毒性破坏，(ii) 癫痫倾向作为 CNS 抑制的探针，(iii) 星形胶质细胞和小胶质细胞的变化，以及 (iv) FOS 标记，用于研究体细胞图谱中的可塑性 Vc 和腰骶神经元池对幕外痛觉过敏部位的急性伤害性刺激做出反应。这些遗传和表型研究被提议作为研究三叉神经疼痛综合征的新的、稳健的模型。识别影响三叉神经疼痛综合征的遗传因素可以提供新的治疗靶点。