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
基本信息
- 批准号:10622997
- 负责人:
- 金额:$ 5.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAdministrative SupplementAdultAdverse effectsAffectAmericanAnalgesicsAnimal ModelAnimalsAnxietyBehavioralBioinformaticsBiological Response ModifiersCardiacCardiotoxicityCaringChronicClinicalCytometryDataDevelopmentDevelopmental ProcessDoseEducationEventExposure toFeedbackFemaleFutureGene Expression ProfileGlucocorticoidsHealthHealth Care CostsHealth behaviorHourHyperalgesiaHypersensitivityImmunologicsIndividualInflammatoryInflammatory ResponseInjuryInterventionLiteratureMeasurementMechanicsMediatingMedicalMental DepressionModelingMolecularPainParentsPatientsPeripheralPharmaceutical PreparationsPhysiologicalPlayPreventionPreventiveProcessProspective StudiesProteinsRNA analysisRecoveryReportingResearch PersonnelRiskRoleSafetyScientistSeveritiesSignal TransductionSpinalStatistical Data InterpretationStressSurgical incisionsSurvivorsSystemTacrolimus Binding ProteinsTimeTissuesTranslational ResearchVehicle crashWorkabuse liabilityaddictionaddiction liabilityanimal dataanimal tissueantagonistbehavioral outcomebiological adaptation to stresscareerchronic paincohortcomorbiditycytokinedesignefficacy evaluationexperienceexperimental studyhigh riskinhibitorinnovationmalemouse modelneuropsychiatric disordernew therapeutic targetopioid misuseopioid usepain chronificationparent grantphysical assaultpost-traumatic stressprescription opioidpreventpublic health relevancesafety testingsexual assaulttherapeutic targettissue injurytraining opportunitytranscriptome sequencingtraumatic stress
项目摘要
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.
项目概要/摘要
创伤性应激暴露(TSE)后产生的疼痛的治疗目标历来集中于
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
应激反应在 TSE 后慢性疼痛发展中发挥着关键作用,开启了令人兴奋的新局面
在这一前景中,没有什么靶点比 FK506 结合更有希望。
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。
研究人员的数据表明,FKBP51 抑制可逆转 TSE 后的痛觉过敏,并表明
TSE 后抑制 FKBP51 可以预防持久性压力诱发的痛觉过敏 (ESIH)。
进一步证明 FKBP51 抑制对 TSE 后 ESIH 的影响是时间、剂量和持续时间-
现有文献表明,FKBP51 水平升高不仅与慢性疼痛有关。
TSE 后,还伴有其他创伤后神经精神疾病,通常与慢性疼痛和
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,来自研究的初步数据。
研究小组表明,FKBP51 抑制不会对心脏产生不良影响或其他不良健康影响
或行为影响。
基于这些数据,母公司 R01 将执行接下来的关键步骤,评估 FKBP51 作为一种治疗药物
目标,包括(1)评估 TSE 后 FKBP51 抑制的剂量、时机和持续时间对
ESIH 开发,(2) 评估介导 FKBP51 抑制的预防作用的候选机制
(3) 对安全性和成瘾倾向进行广泛的测试。
在这份促进多元化的行政补充文件中,候选人将详细阐述拟议的
通过进行范围内但与研究无关的创新实验来进行机械工作
特别是,候选人将进行实验以获得更广泛的资助。
了解 FKBP51 如何影响 TSE 后和跨时间的基因表达模式
候选人还将执行与疼痛过程相关的中枢和外周组织的前沿分子研究。
评估 FKBP51 影响的细胞内信号网络的免疫学研究。
实验以及广泛的培训机会旨在促进候选人的教育和
成功完成研究的未来职业轨迹是成为一名独立的学术科学家。
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理解
FKBP51 影响 TSE 后疼痛发展的分子机制。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Sarah Linnstaedt其他文献
Sarah Linnstaedt的其他文献
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{{ truncateString('Sarah Linnstaedt', 18)}}的其他基金
FKBP51 antagonism to prevent chronic pain: optimizing efficacy & evaluating safety and mechanisms
FKBP51 拮抗剂预防慢性疼痛:优化疗效
- 批准号:
10055490 - 财政年份:2020
- 资助金额:
$ 5.91万 - 项目类别:
Key Molecular Mechanisms of Chronic Pain Vulnerability in Women Experiencing MVC
经历 MVC 的女性慢性疼痛脆弱性的关键分子机制
- 批准号:
9896771 - 财政年份:2018
- 资助金额:
$ 5.91万 - 项目类别:
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