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

项目摘要/摘要 针对创伤应激暴露(TSE)后产生的疼痛的治疗靶点历来是关注的焦点 与组织损伤相关的疼痛发生器，但越来越多的证据表明，生理系统参与了 应激反应在TSE后慢性疼痛的发展中起着关键作用，开辟了一个令人兴奋的新局面 潜在的治疗靶点。在这种情况下，没有比结合FK506更有希望的靶点了 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。这个 研究人员的数据表明，抑制FKBP51可以逆转TSE后的痛觉过敏，并提示 TSE后抑制FKBP51可预防持续性应激性痛觉过敏(ESIH)。调查人员的数据 进一步证明，抑制FKBP51对TSE后ESIH的影响有时间、剂量和持续时间。 依附的。现有文献表明，FKBP51水平升高不仅与慢性疼痛有关 TSE后，但也与其他创伤后神经精神障碍经常合并慢性疼痛和 阿片类药物的使用/滥用，包括创伤后应激、抑郁和焦虑。重要的是，来自 研究小组指出，抑制FKBP51不会对心脏或其他健康造成不利影响 或行为影响。 在这些数据的基础上，母公司R01将执行评估FKBP51作为治疗药物的下一个关键步骤 靶点，包括(1)评估TSE后FKBP51抑制的剂量、时机和持续时间对 ESIH的发展，(2)评估介导FKBP51抑制预防效果的候选机制 关于慢性疼痛的发展，以及(3)进行广泛的安全性和成瘾倾向测试。 在这份促进多样性的行政副刊中，候选人将对拟议的 在研究范围内但不是多余的进行创新实验的机械性工作 在父母拨款中提出的。特别是，候选人将进行实验，以获得更广泛的 了解FKBP51如何随时间影响TSE和TSE后的基因表达模式 与疼痛过程有关的中枢和外周组织。候选人还将表演尖端的分子 评估FKBP51影响的细胞内信号网络的免疫学研究。这些行为的行为 实验和广泛的培训机会，旨在促进候选人的教育和 未来的职业轨迹是成为一名独立的学术科学家。顺利完成研究 在本《多样性行政补编》中提出的建议将推动该领域在理解 FKBP51影响TSE后疼痛发展的分子机制。

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.