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

项目总结/摘要 创伤应激暴露（TSE）后疼痛的治疗目标历来集中在 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 应激反应在TSE后慢性疼痛发展中起着关键作用，这开辟了一个令人兴奋的新领域 潜在的治疗靶点在这种情况下，没有靶点比FK 506结合更有希望。 蛋白51（FKBP 51），已知影响糖皮质激素负反馈抑制的细胞内蛋白。的 研究人员的数据表明，FKBP 51抑制可逆转TSE后的痛觉过敏，并表明 TSE后抑制FKBP 51可预防持久性应激诱导的痛觉过敏（ESIH）。研究者的数据 进一步证明了FKBP 51抑制对TSE后ESIH的影响是时间、剂量和持续时间。 依赖。现有文献表明，FKBP 51水平升高不仅与慢性疼痛相关， 在TSE后，也与其他创伤后神经精神障碍，往往与慢性疼痛和 阿片类药物使用/滥用，包括创伤后应激，抑郁和焦虑。重要的是， 研究小组指出，FKBP 51抑制剂不会对心脏或其他健康产生不利影响 或行为效应。 在这些数据的基础上，母公司R 01将执行下一个关键步骤，以评价FKBP 51作为治疗药物 目标，包括（1）评价TSE后FKBP 51抑制的剂量、时间和持续时间对 ESIH开发，（2）评估介导FKBP 51抑制预防作用的候选机制 对慢性疼痛的发展，和（3）进行广泛的安全性和成瘾倾向的测试。 在这一行政补充，以促进多样性，候选人将扩大对拟议的 通过进行范围内但不与研究重复的创新实验来进行机械工作 在父母补助金中提出。特别是，候选人将进行实验，以获得更广泛的 了解FKBP 51如何影响TSE后不同时间和不同时间的基因表达模式 与疼痛过程相关的中枢和外周组织。候选人还将执行尖端分子 评估受FKBP 51影响的细胞内信号传导网络的免疫学研究。进行这些 实验沿着广泛的培训机会，旨在促进候选人的教育， 未来的职业发展方向是成为一名独立的学术科学家。顺利完成学业 本多样性行政补充文件中提出的建议将推动该领域进一步了解 FKBP 51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.