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 在患有SCD的患者中，疼痛会导致身体和情感上的负面影响。一个 充分解决SCD痛苦的重大障碍是有关基础的足够信息 影响患者经历的可变程度和类型的机制。多生物学和 到目前为止已知有助于其他疼痛状况的心理因素（即环境压力）不足 在SCD学习。精氨酸加压素受体1a是7跨膜结构域G蛋白G蛋白多肽 这涉及压力和疼痛。受体基因启动子（AVPR1A）中的RS10877969 SNP为 与急性疼痛和与压力相关的疼痛的各个方面以及加压素系统有关 调查SCD疼痛的潜在贡献。我将利用几种加压素的现有数据 - 相关的生物/社会心理因素和定量感觉测试（QST）研究这些机制 （以及潜在的相互作用）SCD疼痛。我还将招募一个与SCD的成年人组成的新研究队列 次要的，探索性的目标是对与SCD疼痛相关的无偏基因组进行无偏见的搜索 我们大量特征良好的受试者中的修饰符。我提出了三个具体目标：目标1。 来自172名具有SCD的非裔美国人的数据集，我将进行统计分析：（a）测试协会 在AVPR1A基因型（RS10877969）和SCD实验疼痛值（QST热和机械之间）之间 疼痛阈值），这将决定疼痛阈值是否根据AVPR1A基因型变化（即基因 X环境相互作用）。假设：基因型的热和机械疼痛阈值将有所不同（ 基因型将预测QST疼痛阈值）。 （b）测试SCD临床疼痛之间的关系是否 （API；平均疼痛强度以0-10级测量）和环境压力（PSQ；感知应力 问卷）由RS10877969基因型主持。假设：基因型将影响相关性 在环境压力和临床疼痛之间。目标2。这项工作还将涉及招募和表征 新的50名成年人的SCD组，用于研究加压素系统的其他生物学效应子 机械洞察力：（a）测试疼痛与压力表型的关系（包括QST，API和PSQ） 与AVPR1A基因表达（白细胞AVPR1A mRNA水平通过定量RT-PCR测量），并与 启动子甲基化。 （b）探索精氨酸加压素（替代copeptin）等离子体的变异性 集中和与疼痛和压力的关联。数据将用于计划未来的R01研究。目标3。 作为一项试点发现研究，为了扩大对遗传SCD疼痛修饰剂的搜索，我将执行全基因组 基于疼痛表型（API）的组合患者组（172+50）的关联研究（GWAS）。目标1和 2将阐明加压素系统在SCD疼痛中的作用，并可能为将来的研究提供见解 进入该人群的疼痛的预测和治疗，尤其是与压力有关的人。探索目的5月3日 确定基因和途径在未来的SCD疼痛研究中进一步研究。