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: 8529499
• 负责人: ROY C. LEVITT
• 金额: $ 53.77万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529499
• 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; 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; 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1500亿美元用于超过3000万患有未缓解疼痛的美国人。持续性疼痛治疗不足导致生活质量差，社会和情感功能障碍。现在普遍认为，对持续性疼痛的易感性是一种受多基因影响的复杂遗传性状。最近，常见的遗传基因多态性已被证明会导致疼痛感知的个体差异，并可能成为急性疼痛向持续性疼痛转变的基础。然而，这些变异很少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，更好地定义了从急性疼痛到持续性疼痛转变的可变生物学途径，可以从机制上理解某些形式的持续性疼痛是如何发展的，从而促进更有效的干预措施，极大地影响这些患者和这一领域。我们最近发现，神经元碳酸酐酶8（CA 8）的变化与可变的伤害感受和持续性疼痛小鼠。此外，人类CA 8的生物学变异性与多种流行的持续性疼痛综合征相关，表明CA 8基因座的生物学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。CA 8是神经元三磷酸肌醇受体-1（IP 3R 1）的变构抑制剂，IP 3R 1是细胞内IP 3门控Ca 2+通道。CA 8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，我们将确定和验证功能性CA 8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，包括颞下颌关节病（TMD），伴有广泛疼痛的TMD，坐骨神经痛，疱疹后神经痛（PHN），脊髓损伤（SCI）后神经性疼痛和骨关节炎（OA）。我们将使用最先进的外显子组阵列，包括注释基因（包括CA 8通路基因）中的外显子单核苷酸多态性（SNP），以确定在一个大型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推定的功能变体。然后将在我们的复制队列中对与OA表型相关的假定功能性SNP进行基因分型，包括TMD、坐骨神经痛、PHN和SCI，以测试与持续性疼痛的相关性。在其他持续性疼痛综合征中符合我们的复制标准的SNP的生物学作用将在体外使用功能基因组学建立。我们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性状的遗传解剖方面具有丰富的专业知识，有能力追求与持续性疼痛中CA 8通路变体的鉴定和功能验证相关的创新和高度相关的最先进的科学计划。这项关于从急性疼痛到慢性疼痛过渡的合作研究的结果将导致易感性和治疗反应的生物标志物的改进，以及对持续性疼痛综合征的更好干预。