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

点击翻译按钮获取中文摘要

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.