CA8 Variants: New Mechanisms Underlying Transitions to Persistent Pain Syndromes

描述（由申请人提供）：每年有超过1500亿美元花费在3000多万美国人身上，他们遭受着无法缓解的痛苦。不适当的持续性疼痛治疗会导致生活质量低下，以及社交和情感功能障碍。现在人们普遍认为，对持续性疼痛的易感性是一种复杂的遗传性状，受多种基因的影响。最近，常见的遗传多态性已被证明会导致疼痛感知的个体差异，并可能是急性疼痛向持续性疼痛转变的基础。然而，这些变异几乎不能解释潜在的遗传效应，大多数功能性遗传变异是未知的。精确定位基因和相关变异，更好地定义从急性疼痛到持续性疼痛转变的可变生物学途径，可以产生对某些形式的持续性疼痛如何发展的机制理解，从而促进更有效的干预，极大地影响这些患者和该领域。我们最近的研究表明，神经元碳酸酐酶8 （CA8）的变化与小鼠的可变伤害感觉和持续疼痛有关。此外，人类CA8基因的生物变异与多种普遍存在的持续性疼痛综合征有关，这表明CA8基因位点的生物变异可能在这些难以治疗的综合征的易感性中起着重要的多效性作用。CA8是神经元肌醇三磷酸受体1 （IP3R1）的变构抑制剂，是细胞内ip3门控的Ca2+通道。CA8调节多种钙依赖性神经元活动，如细胞分泌、收缩、突触功能和膜兴奋性。在这个项目中，我们将识别和验证CA8的功能变异，这些变异是一种或多种常见持续性疼痛综合征的易感性基础，包括颞下颌疾病（TMD）、TMD伴广泛性疼痛、坐骨神经痛、疱疹后神经痛（PHN）、脊髓损伤后神经性疼痛（SCI）和骨关节炎（OA）。我们将使用最先进的外显子组阵列，包括注释基因（包括CA8通路基因）的外显子单核苷酸多态性（snp），以识别大型OA队列中与持续疼痛、僵硬、情绪和社会功能相关的snp。接下来将使用最新的生物信息学技术选择假定的功能变体。然后，我们将在包括TMD、坐骨神经痛、PHN和SCI在内的复制队列中对与OA表型相关的假定功能snp进行基因分型，以测试其与持续性疼痛的关联。满足我们复制标准的snp在其他持续性疼痛综合征中的生物学作用将在体外使用功能基因组学建立。我们已经组建了一支优秀的合作团队，他们在基础和临床疼痛研究以及复杂特征的遗传解剖方面拥有丰富的专业知识，有能力追求这一创新和高度相关的最先进的科学计划，这些计划与持续疼痛中CA8通路变异的识别和功能验证有关。这项关于从急性到慢性疼痛转变的合作研究的结果将导致改善易感性和治疗反应的生物标志物，以及对持续疼痛综合征的更好干预。

DESCRIPTION (provided by applicant): Over $150 billion is spent annually on over 30 million Americans suffering with unrelieved pain. Inadequate persistent pain treatments lead to poor quality of life, and social and emotional dysfunctioning. It is now generally accepted that susceptibility to persistent pain is a complex heritable trait influenced by multiple genes. Recently, common inherited genetic polymorphisms have been shown to cause individual differences in pain perception, and may underlie the transition from acute to persistent pain. However, these variants explain very little of the underlying genetic effect and most of the functional genetic variants are unknown. Pinpointing genes and associated variants that better define the variable biologic pathways underlying the transition from acute to persistent pain can yield a mechanistic understanding of how some forms of persistent pain develop facilitating more effective interventions greatly impacting these patients and this field. We have recently shown that variation in neuronal carbonic anhydrase 8 (CA8) is associated with variable nociception and persistent pain in mice. Additionally, biologic variability in human CA8 is associated with multiple prevalent persistent pain syndromes, suggesting biologic variability at the CA8 locus could play an important pleiotropic role in predisposing to these difficult to treat syndromes. CA8 is an allosteric inhibitor of neuronal inositol triphosphate receptor-1 (IP3R1) that is an intracellular IP3-gated Ca2+ channel. CA8 regulates diverse calcium-dependent neuronal activities such as cellular secretion, contraction, synaptic functioning, and membrane excitability. In this project, we will identify and validate functional CA8 variants that underlie susceptibility to one or more common persistent pain syndromes including temporomandibular disease (TMD), TMD with widespread pain, sciatica, post-herpetic neuralgia (PHN), neuropathic pain after spinal cord injury (SCI), and osteoarthritis (OA). We will use state-of-the-art exome arrays comprising exonic single nucleotide polymorphisms (SNPs) in annotated genes (including CA8 pathway genes) to identify SNPs associated with persistent pain, stiffness and emotional and social functioning in a large OA cohort. This will be followed by the selection of putative functional variants using the latest bioinformatics techniques. Presumed functional SNPs associated with the OA phenotype will then be genotyped in our replication cohorts including TMD, sciatica, PHN, and SCI to test for association with the persistent pain. The biologic role of SNPs meeting our replication criteria in the other persistent pain syndromes will then be established using functional genomics in vitro. We have assembled an outstanding collaborative team with great expertise in basic and clinical pain research and the genetic dissection of complex traits, with the ability to pursue this innovative and highly relevant state-f-the-art scientific plan related to the identification and functional validation of CA8 pathway variants in persistent pain. The results of this Collaborative Research on Transitions From Acute to Chronic Pain will lead to improved biomarkers of susceptibility and therapeutic response, and better interventions for persistent pain syndromes.