GENETICS OF NEUROPATHIC & INFLAMMATORY HYPERSENSITIVITY

神经病遗传学

• 批准号: 7674509
• 负责人: WILLIAM Roger LARIVIERE
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674509
• 关键词: Absence of pain sensation; Affect; Animals; Area; Arts; Bee Venoms; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; Chromosome Mapping; Chronic; Chung model; Clinical; Computer Simulation; Data; Databases; Detection; Edema; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Human; Hypersensitivity; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Ligation; Lumbar nerve; Maps; Mechanics; Modeling; Mouse Strains; Mus; Neuropathy; Nociception; Other Genetics; Pain; Phenotype; Population; Predisposition; Prosencephalon; Protocols documentation; Quantitative Trait Loci; Recombinants; Research Personnel; Source; Spinal nerve structure; Subcutaneous Injections; Surveys; Susceptibility Gene; Techniques; Testing; Tissues; Transcript; United States; Venoms; allodynia; chronic neuropathic pain; clinically relevant; genetic analysis; genome-wide; inflammatory neuropathic pain; mechanical allodynia; nerve injury; nociceptive response; novel; painful neuropathy; phenomics; programs; response; subcutaneous; therapy development; tool; trait

DESCRIPTION (provided by applicant): Chronic pain of neuropathic or inflammatory origins affects millions of sufferers in the United States for whom current therapies are inadequate. Because genetic factors significantly contribute to variability among individuals in prolonged pain sensitivity and susceptibility, gene mapping these traits will be useful for the determination of novel and predisposing genetic mechanisms in humans. Thus, this proposal will map the genes underlying variable susceptibility to partial nerve-injury induced hypersensitivity that mimics a common cause of neuropathic pain. Of the multiple pain responses to inflammation, only sensitivity to the immediate, spontaneous nociceptive response has been gene mapped. Thus, this proposal will map the genes under- lying prolonged inflammation-induced hypersensitivity. The genetic model of BXD recombinant inbred (Rl) mice will be used to perform quantitative trait locus (QTL) gene mapping of hypersensitivity to identify regions of the genome containing genes variants associated with variability in the traits. The Specific Aims will test the hypothesis that the genetic mechanisms underlying these traits are distinct from those responsi- ble for all other classes of nociception and hypersensitivity, including all models previously gene mapped. In Specific Aim 1, QTL gene mapping of mechanical sensitivity before, and of mechanical hypersensitivity (allodynia) after, ligation of the fifth lumbar nerve will be performed by surveying the sensitivity of 45 strains of Rl mice of known genotype. QTL mapping will proceed without further genotyping in this proposal due to the continually expanding publicly available genotype data for these mice. In Specific Aim 2, QTL mapping will be similarly performed of spontaneous inflammatory nociception and thermal hypersensitivity following subcutaneous injection of melittin, the major algogenic and inflammatory component of honeybee venom. Due to the use of the BXD Rl mice with known, fixed genotype, single genetic mechanisms responsible for variability in the traits will be immediately determined in Specific Aim 3 by covariance analysis with transcript levels in the forebrain and other brain areas and tissues for which data already exist. In addition, sharing of genetic mechanisms between the hypersensitivity traits and previously studied pain traits and non-pain traits will be determined. These data will be used to determine novel genetic mechanisms of chronic neuropathic and inflammatory pain for predisposition assessment and treatment development.

描述（由申请人提供）：神经性或炎症起源的慢性疼痛会影响美国当前疗法不足的数百万患者。由于遗传因素在长时间的疼痛敏感性和敏感性中显着导致个体之间的变异性，因此基因映射这些特征将有助于确定人类的新颖和易感遗传机制。因此，该提案将绘制对部分神经伤害的可变敏感性的基因，从而诱发了超敏反应，这模仿了神经性疼痛的常见原因。在对炎症的多种疼痛反应中，仅对直接的，自发的伤害感反应的敏感性进行了映射。因此，该提案将绘制延长炎症引起的超敏反应的基因。 BXD重组亲植物（RL）小鼠的遗传模型将用于执行超敏反应的定量性状基因座（QTL）基因映射，以鉴定包含与性状变异性相关的基因组变异的基因组变异区域。具体的目的将检验以下假设：这些特征的基本遗传机制与所有其他类别的伤害感受和超敏反应的遗传机制不同，包括先前基因映射的所有模型。在特定的目标1中，QTL基因映射之前的机械灵敏度和机械性超敏反应（异常性）之后，将通过测量已知基因型RL小鼠的45个菌株的敏感性来进行第五腰神经的连接。由于这些小鼠的公开可用的基因型数据不断扩展，因此将在本提案中进行QTL映射，而无需进一步的基因分型。在特定的目标2中，QTL映射将类似地通过皮下注射蜂蜜素的主要算法和炎症成分的皮下注射后自发性炎症伤害感受和热过敏性进行。由于使用BXD RL小鼠具有已知的固定基因型，因此，通过协方差分析，将立即在特定的目标3中确定负责性状可变性的单个遗传机制，并在前脑和其他大脑区域和其他已经存在的数据中具有转录水平。此外，将确定超敏性特征与先前研究的疼痛性状和非呼吸特征之间的遗传机制共享。这些数据将用于确定慢性神经性疼痛和炎症性疼痛的新遗传机制，以进行倾向评估和治疗发育。