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: 8118256
• 负责人: Ze 'ev Y. Seltzer
• 金额: $ 24.97万
• 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/8118256
• 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; Inbreeding; Individual Differences; Injury; Ion Channel; 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（由申请人提供）：为了测试三叉神经痛是复杂遗传性状的假说，我们最近通过单侧切断眶下神经（IONX）产生了一种新的颅面神经性疼痛（CNP）小鼠模型。我们发现轻触会疼痛（即，异常性疼痛）和对有害刺激的疼痛增加（即，痛觉过敏）出现在两个耳朵，爪和尾巴，并依赖于性别和所研究的菌株的遗传背景。该模型是一个强大的平台，可以研究CNP的遗传机制，这种机制在人类，特别是女性中经常出现。我们的具体目标是确定候选的遗传因素，有助于对CNP的易感性差异。由于其中一些可能编码电压门控和配体门控离子通道基因，因此在AIM-1中，我们将在20个近交小鼠品系中识别235个此类基因中的SNP，并重建它们的单倍型。AIM-2：在这些小鼠中对CNP进行IONX后的表型分析以及对其单倍型图谱进行计算遗传分析，我们将确定控制CNP的遗传因素。对23个AXB-BXA重组近交系小鼠进行表型分析，然后对其已知的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，我们将确定差异表达的基因在三叉神经尾侧亚核（Vc）的菌株对比CNP水平后IONX。这3个图谱的叠加应能够鉴别CNP的候选基因。不属于本研究的一部分，我们将在三叉神经（和其他）神经性疼痛患者队列中对这些基因进行基因分型。AIM-3：在AIM 2中分型的43株菌株中的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CNS可塑性的机制，测试新型镇痛剂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，以确定神经损伤后与CNP和未确定的中枢可塑性相关的性状：（i）Vc中疼痛抑制神经元的兴奋性毒性破坏，（ii）作为CNS抑制探针的癫痫倾向，（iii）星形胶质细胞和小胶质细胞的变化，和（四）用FOS标记研究视丘和腰骶神经元池对幕外部位急性伤害性刺激的躯体反应图的可塑性痛觉过敏这些基因和表型研究提出了一个新的和强大的模型来研究三叉神经疼痛综合征。识别影响三叉神经痛综合征的遗传因素可以提供新的治疗靶点。