Contributions of biopsychosocial factors in sickle cell disease pain

生物心理社会因素对镰状细胞病疼痛的影响

• 批准号: 10530915
• 负责人: Keesha L. Roach
• 金额: $ 13.46万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530915
• 关键词: Contributions; biopsychosocial; factors; sickle; cell

Abstract In patients with SCD, pain results in an amalgam of negative physical and emotional consequences. A significant barrier to adequately address the pain of SCD is the insufficient information about underlying mechanisms affecting the variable degree and types of pain experienced by patients. Multiple biological and psychological factors (i.e., environmental stress) known so far to contribute to other pain conditions are under- studied in SCD. The arginine vasopressin receptor 1A is a 7-transmembrane domain G-protein polypeptide that is involved in stress and pain. The rs10877969 SNP in the receptor gene promoter (AVPR1A) is associated with aspects of acute pain and stress-related pain and the vasopressin system warrant further investigation into potential contributions to pain in SCD. I will utilize existing data for several vasopressin- related biological/psychosocial factors and quantitative sensory testing (QST) to investigate these mechanisms (and potential interactions) in SCD pain. I will also recruit a new study cohort of adults with SCD for a secondary, exploratory goal of performing an unbiased genome-wide search for SCD pain-related genetic modifiers in our large set of well-characterized subjects. I propose three specific aims: Aim 1. In an established data set from of 172 African Americans with SCD, I will perform statistical analysis: (a) To test for associations between AVPR1A genotype (rs10877969) and SCD experimental pain values (QST thermal and mechanical pain thresholds), which will determine whether pain thresholds vary based on AVPR1A genotype (i.e., a gene X environment interaction). Hypothesis: Thermal and mechanical pain thresholds will differ by genotype (the genotype will predict the QST pain thresholds). (b) To test whether the relationship between SCD clinical pain (API; Average Pain Intensity measured on 0-10 scale) and environmental stress (PSQ; Perceived Stress Questionnaire) is moderated by the rs10877969 genotype. Hypothesis: Genotype will influence the correlation between environmental stress and clinical pain. Aim 2. This work will also involve recruiting and characterizing a new cohort of 50 adults with SCD to study additional biological effectors of the vasopressin system for mechanistic insight: (a) To test for relationship of pain and stress phenotypes (including QST, API and PSQ) with AVPR1A gene expression (leukocyte AVPR1A mRNA levels measured by quantitative RT-PCR) and with promoter methylation. (b) To explore the variability in arginine vasopressin (surrogate copeptin) plasma concentration and associations with pain and stress. The data will be used to plan a future R01 study. Aim 3. As a pilot discovery study, to expand the search for genetic SCD pain modifiers, I will perform genome-wide association studies (GWAS) in the combined patient set (172+50) based on pain phenotype (API). Aims 1 and 2 will shed light on the role of the vasopressin system in SCD pain, and may provide insight for future studies into prediction and treatment of pain in this population, particularly stress-related. Exploratory Aim 3 may identify genes and pathways to investigate further in future studies of SCD pain.

抽象的 对于 SCD 患者来说，疼痛会导致身体和情感上的负面后果。一个 充分解决 SCD 痛苦的一个重要障碍是关于潜在问题的信息不足 影响患者所经历的不同程度和类型的疼痛的机制。多种生物和 迄今为止，已知的导致其他疼痛状况的心理因素（即环境压力）尚不明确。 在SCD学习。精氨酸加压素受体 1A 是一种 7 跨膜结构域 G 蛋白多肽 这涉及压力和痛苦。受体基因启动子（AVPR1A）中的rs10877969 SNP是 与急性疼痛和压力相关疼痛以及加压素系统相关的方面需要进一步研究 调查对 SCD 疼痛的潜在影响。我将利用几种加压素的现有数据- 相关的生物/心理社会因素和定量感官测试（QST）来研究这些机制 （和潜在的相互作用）SCD 疼痛。我还将招募一组新的患有 SCD 的成年人进行研究 第二个探索性目标是对 SCD 疼痛相关基因进行公正的全基因组搜索 我们大量特征鲜明的主题中的修饰语。我提出三个具体目标： 目标 1. 在既定的框架内 数据集来自 172 名患有 SCD 的非裔美国人，我将进行统计分析：(a) 测试关联 AVPR1A 基因型 (rs10877969) 和 SCD 实验疼痛值（QST 热和机械）之间的差异 疼痛阈值），这将确定疼痛阈值是否根据 AVPR1A 基因型（即基因 X 环境交互）。假设：热痛阈值和机械痛阈值因基因型（基因型）的不同而不同（ 基因型将预测 QST 疼痛阈值）。 (b) 检验SCD临床疼痛之间是否有关系 （API；按 0-10 等级测量的平均疼痛强度）和环境压力（PSQ；感知压力 问卷）由 rs10877969 基因型调节。假设：基因型会影响相关性 环境压力和临床疼痛之间的关系。目标 2. 这项工作还将涉及招募和表征 一个由 50 名患有 SCD 的成年人组成的新队列研究加压素系统的其他生物效应器 机制洞察：(a) 测试疼痛和压力表型的关系（包括 QST、API 和 PSQ） AVPR1A 基因表达（通过定量 RT-PCR 测量白细胞 AVPR1A mRNA 水平）和 启动子甲基化。 (b) 探讨血浆精氨酸加压素（替代和肽素）的变异性 注意力以及与疼痛和压力的关联。这些数据将用于规划未来的 R01 研究。目标3。 作为一项试点发现研究，为了扩大对遗传性 SCD 疼痛调节剂的搜索，我将进行全基因组研究 基于疼痛表型 (API) 在组合患者组 (172+50) 中进行关联研究 (GWAS)。目标 1 和 2 将阐明加压素系统在 SCD 疼痛中的作用，并可能为未来的研究提供见解 预测和治疗该人群的疼痛，特别是与压力相关的疼痛。探索性目标 5 月 3 日 确定基因和通路，以便在未来的 SCD 疼痛研究中进一步研究。