Diversity Supplement to FKBP51 antagonism to prevent chronic pain: optimizing efficacy & evaluating safety and mechanisms R01NS118563

FKBP51 拮抗剂的多样性补充可预防慢性疼痛：优化疗效

• 批准号: 10622997
• 负责人: Sarah Linnstaedt
• 金额: $ 5.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622997
• 关键词: Acute; Administrative Supplement; Adult; Adverse effects; Affect; American; Analgesics; Animal Model; Animals; Anxiety; Behavioral; Bioinformatics; Biological Response Modifiers; Cardiac; Cardiotoxicity; Caring; Chronic; Clinical; Cytometry; Data; Development; Developmental Process; Dose; Education; Event; Exposure to; Feedback; Female; Future; Gene Expression Profile; Glucocorticoids; Health; Health Care Costs; Health behavior; Hour; Hyperalgesia; Hypersensitivity; Immunologics; Individual; Inflammatory; Inflammatory Response; Injury; Intervention; Literature; Measurement; Mechanics; Mediating; Medical; Mental Depression; Modeling; Molecular; Pain; Parents; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Prevention; Preventive; Process; Prospective Studies; Proteins; RNA analysis; Recovery; Reporting; Research Personnel; Risk; Role; Safety; Scientist; Severities; Signal Transduction; Spinal; Statistical Data Interpretation; Stress; Surgical incisions; Survivors; System; Tacrolimus Binding Proteins; Time; Tissues; Translational Research; Vehicle crash; Work; abuse liability; addiction; addiction liability; animal data; animal tissue; antagonist; behavioral outcome; biological adaptation to stress; career; chronic pain; cohort; comorbidity; cytokine; design; efficacy evaluation; experience; experimental study; high risk; inhibitor; innovation; male; mouse model; neuropsychiatric disorder; new therapeutic target; opioid misuse; opioid use; pain chronification; parent grant; physical assault; post-traumatic stress; prescription opioid; prevent; public health relevance; safety testing; sexual assault; therapeutic target; tissue injury; training opportunity; transcriptome sequencing; traumatic stress

PROJECT SUMMARY/ABSTRACT Therapeutic targets for pain that develops following traumatic stress exposures (TSE) have historically focused on tissue injury-related pain generators, but increasing evidence suggests that physiologic systems involved in the stress response play a critical role in chronic pain development after TSE, opening an exciting new landscape of potential therapeutic targets. Within this landscape, no target appears more promising than FK506-binding protein 51 (FKBP51), an intracellular protein known to affect glucocorticoid negative feedback inhibition. The investigators’ data demonstrate that FKBP51 inhibition reverses hyperalgesia after TSE, and suggest that FKBP51 inhibition after TSE can prevent enduring stress-induced hyperalgesia (ESIH). The investigators’ data further demonstrate that the effects of FKBP51 inhibition on ESIH after TSE are time, dosing, and duration- dependent. Available literature indicate that increased FKBP51 levels are associated not only with chronic pain after TSE, but also with other post-traumatic neuropsychiatric disorders often comorbid with chronic pain and opioid use/abuse, including posttraumatic stress, depression, and anxiety. Importantly, preliminary data from the investigative team indicate that FKBP51 inhibition does not have adverse cardiac effects or other adverse health or behavioral effects. Building on these data, the parent R01 will perform the next critical steps in evaluating FKBP51 as a therapeutic target, including (1) evaluating the influence of dose, timing, and duration of FKBP51 inhibition after TSE on ESIH development, (2) assessing candidate mechanisms mediating the preventive effect of FKBP51 inhibition on chronic pain development, and (3) performing extensive testing of safety and addiction liability. In this Administrative Supplement to Promote Diversity, the candidate will expand upon the proposed mechanistic work by performing innovative experiments that are within the scope but not redundant with studies proposed in the parent grant. In particular, the candidate will perform experiments to gain a broader understanding of how FKBP51 influences gene expression patterns across time following TSE and across central and peripheral tissues related to pain processes. The candidate will also perform cutting edge molecular immunological studies assessing intracellular signaling networks influenced by FKBP51. The conduct of these experiments along with extensive training opportunities, are designed to promote the candidate’s education and future career trajectory toward being an independent academic scientist. Successful completion of the studies proposed in this Administrative Supplement for Diversity will move the field forward in understanding the molecular mechanisms by which FKBP51 influences post-TSE pain development.

项目摘要/摘要 在创伤压力暴露（TSE）之后，疼痛的治疗靶标有历史上的重点 关于组织损伤相关的疼痛发生器，但越来越多的证据表明，参与的生理系统 压力反应在TSE之后的慢性疼痛发展中起着关键作用，打开了令人兴奋的新景观 潜在的治疗靶标。在这个景观中，没有比FK506结合的目标更多的目标 蛋白51（FKBP51），一种已知影响糖皮质激素负反馈抑制的细胞内蛋白。这 研究者的数据表明，FKBP51抑制作用会逆转TSE之后的痛觉过敏，并建议 TSE后的FKBP51抑制可以防止持久压力诱导的痛觉过敏（ESIH）。调查人员的数据 进一步表明，FKBP51对TSE后ESIH的抑制作用是时间，剂量和持续时间 - 依赖。可用文献表明，FKBP51水平升高不仅与慢性疼痛有关 在TSE之后，但也与其他创伤后神经精神疾病有关，通常与慢性疼痛和 Oopioid使用/滥用，包括创伤后压力，抑郁和焦虑。重要的是，来自 调查团队表明FKBP51抑制没有不良心脏影响或其他不良健康 或行为影响。 在这些数据的基础上，父级R01将在评估FKBP51作为疗法的下一个关键步骤 目标，包括（1）评估TSE抑制剂量，时机和持续时间的影响 ESIH开发，（2）评估介导FKBP51的预防作用的候选机制 关于慢性疼痛的发展，以及（3）对安全性和成瘾责任进行广泛的测试。 在这种促进多样性的行政补充中，候选人将扩展到拟议的 通过进行范围内但不冗余的创新实验来进行机械工作 在父母赠款中提议。特别是，候选人将执行实验以获得更广泛的 了解FKBP51如何影响TSE和整个TSE的时间之间的基因表达模式 与疼痛过程有关的中央和周围组织。候选人还将执行尖端分子 评估受FKBP51影响的细胞内信号网络的免疫学研究。这些行为 实验以及广泛的培训机会，旨在促进候选人的教育和 未来的职业发展轨迹，成为一名独立的学术科学家。成功完成研究 在这种多样性的行政补充中提出的提议将推动该领域的前进，以理解 FKBP51影响TSE疼痛后发育后的分子机制。