CA8 Variants: New Mechanisms Underlying Transitions to Persistent Pain Syndromes

CA8 变体：向持续性疼痛综合征转变的新机制

• 批准号: 8891937
• 负责人: ROY C. LEVITT
• 金额: $ 47.98万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891937
• 关键词: Acute; American; Animals; Arts; Binding; Bioinformatics; Biological Assay; Biological Markers; Calcium; Calcium Signaling; Cell secretion; Clinical; Complex; Computer Simulation; DNA; Data; Degenerative polyarthritis; Dental; Disease; Disease susceptibility; Dissection; Economic Burden; Emotional; Functional disorder; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genome; Genomic approach; Genomics; Genotype; Health; Human; ITPR1 gene; In Vitro; Individual Differences; Inherited; Inositol; Interdisciplinary Study; Intervention; Lead; Measures; Medical; Membrane; Methods; Monitor; Morbidity - disease rate; Mus; Neurons; Nociception; Oral; Orofacial Pain; Pain; Pain Research; Pathway interactions; Patients; Perception; Persistent pain; Phenotype; Play; Population; Postherpetic neuralgia; Predisposition; Productivity; Proteins; Quality of life; Research; Role; Sciatica; Signal Transduction; Single Nucleotide Polymorphism; Social Functioning; Spinal cord injury; Syndrome; Techniques; Temporomandibular Joint Disorders; Testing; Therapeutic; Time; TimeLine; Validation; Variant; Western Ontario and McMaster Universities Arthritis Index; Work; base; carbonate dehydratase; chronic pain; chronic widespread pain; cohort; cost; craniofacial; design; disability; effective intervention; exome; functional genomics; genetic variant; genome-wide; improved; inhibitor/antagonist; innovation; inositol 3-phosphate; meetings; multidisciplinary; novel; painful neuropathy; programs; receptor; response; risk variant; social; synaptic function; trait; tripolyphosphate

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.

描述（由申请人提供）：每年花费超过 1,500 亿美元用于治疗超过 3,000 万遭受无法缓解的痛苦的美国人。持续性疼痛治疗不充分会导致生活质量差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受多个基因影响的复杂遗传性状。最近，常见的遗传性基因多态性已被证明会导致疼痛感知的个体差异，并可能是从急性疼痛向持续性疼痛转变的基础。然而，这些变异很少能解释潜在的遗传效应，而且大多数功能性遗传变异都是未知的。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途径，可以从机制上理解某些形式的持续性疼痛如何发展，从而促进更有效的干预措施，极大地影响这些患者和该领域。我们最近发现，神经元碳酸酐酶 8 (CA8) 的变异与小鼠不同的伤害感受和持续性疼痛有关。此外，人类 CA8 的生物变异性与多种流行的持续性疼痛综合征相关，表明 CA8 基因座的生物变异性可能在诱发这些难以治疗的综合征中发挥重要的多效性作用。 CA8 是神经元肌醇三磷酸受体 1 (IP3R1) 的变构抑制剂，IP3R1 是细胞内 IP3 门控 Ca2+ 通道。 CA8 调节多种钙依赖性神经元活动，例如细胞分泌、收缩、突触功能和膜兴奋性。在这个项目中，我们将识别和验证功能性 CA8 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，包括颞下颌疾病 (TMD)、TMD 广泛疼痛、坐骨神经痛、带状疱疹后神经痛 (PHN)、脊髓后神经性疼痛损伤（SCI）和骨关节炎（OA）。我们将使用最先进的外显子组阵列，其中包含注释基因（包括 CA8 通路基因）中的外显子单核苷酸多态性 (SNP)，以识别大型 OA 队列中与持续性疼痛、僵硬以及情绪和社会功能相关的 SNP。随后将使用最新的生物信息学技术选择假定的功能变体。然后，将在我们的复制队列（包括 TMD、坐骨神经痛、PHN 和 SCI）中对假定的与 OA 表型相关的功能性 SNP 进行基因分型，以测试与持续性疼痛的关联。然后，将使用体外功能基因组学来确定符合我们的复制标准的 SNP 在其他持续性疼痛综合征中的生物学作用。我们组建了一支优秀的合作团队，在基础和临床疼痛研究以及复杂性状的基因解剖方面拥有丰富的专业知识，有能力追求与识别和功能验证相关的创新且高度相关的最先进科学计划CA8 通路变异在持续性疼痛中的作用。这项关于从急性疼痛到慢性疼痛转变的合作研究的结果将改善易感性和治疗反应的生物标志物，并更好地干预持续性疼痛综合征。