Sexually dimorphic pain signaling mechanisms

性别二态性疼痛信号机制

• 批准号: 10704129
• 负责人: Christopher Ryan Donnelly
• 金额: $ 53.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704129
• 关键词: American; Anxiety; Biological; Biological Markers; Biological Response Modifier Therapy; Chronic; Clinical; Exhibits; Fatigue; Feeling suicidal; Female; Fibromyalgia; High Prevalence; Hypersensitivity; Immune; Impaired cognition; Impaired health; Individual; Investigation; Mediator; Mental Depression; Mental Health; Methods; Migraine; Molecular; Pain; Pathogenesis; Patient Care; Patients; Personal Satisfaction; Persons; Phenotype; Proteins; Proteomics; Research; Sleep Deprivation; Stimulus; Symptoms; Technology; Temporomandibular Joint Disorders; Testing; anxiety symptoms; cell type; chronic pain; chronic pain patient; chronic painful condition; cohort; comorbidity; depressive symptoms; functional disability; improved; individual patient; insight; male; novel; pain sensitivity; pain signal; patient variability; personalized approach; poor health outcome; pre-clinical; psychologic; psychological distress; screening; sex; sexual dimorphism; side effect; statistics; symptom cluster; transcriptomics

ABSTRACT Although many people are familiar with the staggering statistic that up to 30% of Americans suffer from chronic pain, a less-known fact is that most individuals with chronic pain suffer from more than one comorbid pain condition. Pain conditions which frequently co-aggregate have come to be known as chronic overlapping pain conditions (COPCs). Co-aggregation of multiple chronic pain conditions frequently results in negative side effects in addition to pain, including fatigue, sleep deficits, cognitive impairment, functional impairment, and mental health conditions such as depression, anxiety, and even suicidal ideation. Given the complexity of these side effects and their impact on patient well-being, COPCs have worse health outcomes compared to patients with a single chronic pain condition. In addition, the majority of individual COPCs such as temporomandibular joint disorders (TMD), fibromyalgia (FM), and migraines have a higher prevalence in biological females than in biological males, and their coaggregation is likewise higher in females. Thus, it is imperative that additional research investigations be undertaken which explores the mechanistic determinants of COPCs in patients with multiple comorbid conditions, and which critically evaluates the underlying mechanisms in biological males and females. We have developed methods that use clinical, biological, and psychological patient variables to group patients with COPCs into distinct patient clusters: (1) an “adaptive” cluster, which is free of hypersensitivity and psychological distress; (2) a “pain-sensitive” cluster, which has increased pain sensitivity to pain stimuli, but lacks pain-related comorbidities; and (3) a “global symptoms” cluster of patients which has increased sensitivity to pain, along with multiple symptoms of depression and anxiety, and other widespread symptoms. By separating phenotypically distinct COPC patients and analyzing these cohorts as separate entities individually in males and females, we believe we can better understand these conditions and create a more personalized approach to patient care, which will ultimately improve our ability to treat patients with multiple chronic pain conditions. Our overall hypothesis is that patients within each cluster will exhibit a greater degree of similarity in their cellular and molecular makeup compared to patients in other clusters, and we can exploit these cluster-related differences to identify biological markers and treatment approaches that are personalized for each patient group. To test this hypothesis, we will employ proteomic, transcriptomic, and preclinical screening approaches to ascertain molecular and cellular mediators of pain in individual patient clusters and in each sex. In doing so, this project will yield new mechanistic insights into the divergent pathophysiological mechanisms that give rise to pain and its associated comorbidities in males and females.

抽象的 尽管许多人都熟悉高达 30% 的美国人患有慢性病的惊人统计数据 疼痛，一个鲜为人知的事实是，大多数患有慢性疼痛的人患有不止一种共病疼痛 健康）状况。经常同时聚合的疼痛被称为慢性重叠疼痛 条件（COPC）。多种慢性疼痛的共同聚集经常会产生负面影响 除疼痛外，还会产生疲劳、睡眠不足、认知障碍、功能障碍等影响 心理健康问题，如抑郁、焦虑，甚至自杀意念。鉴于复杂性 考虑到这些副作用及其对患者健康的影响，与其他药物相比，COPC 的健康结果更差 患有单一慢性疼痛的患者。此外，大多数个人 COPC，例如 颞下颌关节紊乱病 (TMD)、纤维肌痛 (FM) 和偏头痛在以下人群中的患病率较高 生物学上的女性比生物学上的男性要多，并且它们的共聚集在女性中同样更高。因此，它是 必须进行额外的研究调查来探索其机制决定因素 患有多种合并症的患者中 COPC 的数量，并严格评估潜在的 生物男性和女性的机制。我们开发了利用临床、生物学和 心理患者变量将 COPC 患者分为不同的患者组：(1) “适应性” 集群，没有超敏反应和心理困扰； (2)“疼痛敏感”簇， 对疼痛刺激的疼痛敏感性增加，但缺乏与疼痛相关的合并症； (3)“整体症状” 一群对疼痛更加敏感的患者，并伴有多种抑郁症状和 焦虑和其他普遍症状。通过分离表型不同的 COPC 患者并分析 这些群体在男性和女性中分别作为独立的实体，我们相信我们可以更好地理解 这些条件并创造一种更加个性化的患者护理方法，这最终将改善我们的 能够治疗患有多种慢性疼痛的患者。我们的总体假设是每个患者 与患者相比，该簇的细胞和分子组成将表现出更大程度的相似性。 其他集群，我们可以利用这些与集群相关的差异来识别生物标记和治疗 针对每个患者群体的个性化方法。为了检验这个假设，我们将采用蛋白质组学， 转录组和临床前筛选方法以确定疼痛的分子和细胞介质 个别患者群体和每个性别。在此过程中，该项目将产生新的机制见解 引起男性和女性疼痛及其相关合并症的不同病理生理机制 女性。