Examination of sex hormone alteration on post-operative pain development and treatment

检查性激素变化对术后疼痛发展和治疗的影响

• 批准号: 10714692
• 负责人: Jenny Wilkerson
• 金额: $ 38.75万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714692
• 关键词: Address; Affect; Analgesics; Behavior; Behavioral; Chronic; Clinical; Depressed mood; Development; Drug Kinetics; Etiology; Genetic; Genome; Genomics; Goals; Gonadal Steroid Hormones; Gonadal structure; Hormones; Human; Individual; Knowledge; Laboratories; Maintenance; Measures; Modeling; Molecular; Moods; Mutation; Operative Surgical Procedures; Pain; Pain management; Play; Population; Positioning Attribute; Postoperative Pain; Predisposition; Recovery; Rodent Model; Role; Surgical incisions; Tissues; Translating; Vulnerable Populations; Whole Organism; Work; antinociception; chronic pain; experience; genome-wide; healing; improved; in vivo monitoring; insight; mouse model; novel; pain model; patient population; pharmacologic; pre-clinical; preclinical study

PROJECT SUMMARY/ABSTRACT Chronic postoperative pain affects a small but significant surgery population. The goal of this project is to preclinically translate and determine the overall contribution of altered sex hormone levels in vulnerable patient populations. These studies will generate novel preclinical sex hormone-altered pharmacological models. This project may identify new insights into those susceptible to developing chronic postoperative pain as well as a greater understanding into underlying genetic and genomic mechanisms. Although many individuals with underlying altered sex hormone levels undergo surgical procedures, most preclinical studies do not attempt to address this highly relevant patient population. As it is well documented that sex hormones play pivotal roles in pain development and maintenance, this is striking. In particular, the role of basally altered sex hormones in gonad-intact preclinical post-surgical pain models is relatively unknown and understudied. Furthermore, the genome-wide and tissue-specific genetic changes that sex hormone alterations may produce before, during, and after surgery have yet to be elucidated. Precise manipulation of hormone levels to establish chronic post-surgical pain causation is not possible in humans. To identify targets for improved post-surgical recovery we will therefore take advantage of a clinically informed sex hormone altered rodent models as well as validated behavioral endpoints. Our central hypothesis is that within vulnerable patient populations, sex hormone alterations occur, contribute to changes in mood, and both sex hormone alterations and mood changes predispose those vulnerable individuals towards post-surgical chronic pain. To pursue this fundamental work, we will use a combination of molecular and whole organism approaches in which I have significant expertise including mouse models of incisional surgery, pain-evoked and pain-depressed behavioral readouts, as well as examination of fold-changes related to both the genome and specific tissues. This convergence of capabilities uniquely positions my independent laboratory to answer key knowledge gaps: 1) Sex hormones are critical in the development and maintenance of chronic pain, but can pharmacological modulation be monitored in vivo via pharmacokinetic measures to identify correlative pain-related behaviors? 2) What specific genetic alterations occur due to sex hormone alterations? 3) Are the sex hormone alterations seen within the surgical patient population relevant to the use and potency of post- surgical analgesics? Ultimately, these studies will establish how sex hormone alterations may influence post- surgical pain recovery. Successful completion of the proposed studies may enhance our understanding of sex hormone alterations within vulnerable patient populations, and the role of sex hormones on healing after surgery, identify associated -omics related changes, and clarify analgesic treatment options.

项目概要/摘要 慢性术后疼痛影响一小部分但重要的手术人群。该项目的目标是 临床前转化并确定易受影响患者性激素水平改变的总体贡献 人口。这些研究将产生新的临床前性激素改变药理学模型。这 该项目可能会对那些易患慢性术后疼痛的人以及 更好地了解潜在的遗传和基因组机制。 尽管许多性激素水平潜在改变的个体接受了外科手术， 大多数临床前研究并不试图解决这一高度相关的患者群体。既然这样就好了 有文献记载，性激素在疼痛的发展和维持中发挥着关键作用，这一点令人震惊。在 特别是，基础改变的性激素在性腺完整的临床前术后疼痛模型中的作用是 相对不为人所知且未被充分研究。此外，全基因组和组织特异性的遗传变化 手术前、手术中和手术后可能产生的性激素改变尚未阐明。精确的 在人类中，操纵激素水平来确定慢性术后疼痛的原因是不可能的。到 确定改善术后恢复的目标，因此我们将利用临床知情的性别 激素改变了啮齿动物模型以及经过验证的行为终点。我们的中心假设是，在 易受伤害的患者群体，性激素会发生变化，导致情绪和性别的变化 激素改变和情绪变化使那些脆弱的个体容易患上术后慢性病 疼痛。为了开展这项基础工作，我们将结合分子和整个生物体 我拥有丰富专业知识的方法，包括切口手术的小鼠模型、疼痛诱发模型 和疼痛抑制行为读数，以及与基因组相关的倍数变化的检查 和特定组织。这种能力的融合使我的独立实验室能够独特地回答 主要知识差距：1）性激素对于慢性疼痛的发展和维持至关重要，但是 是否可以通过药代动力学测量来监测体内药理调节以确定相关性 与疼痛相关的行为？ 2) 性激素改变会导致哪些特定的基因改变？ 3) 是 手术患者群体中观察到的性激素变化与术后药物的使用和效力相关 手术镇痛药？最终，这些研究将确定性激素的改变如何影响术后 手术疼痛恢复。成功完成拟议的研究可能会增强我们对性的理解 易受影响的患者群体中的激素变化，以及性激素对术后愈合的作用 手术，确定相关的组学相关变化，并阐明镇痛治疗方案。