Developing Chemical Probes for Inflammatory Pain

开发炎症性疼痛的化学探针

基本信息

批准号：
10670760
负责人：
Bahaa ElDien Elgendy
金额：
$ 62.5万
依托单位：
ST. LOUIS COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670760
关键词：
Adrenal Cortex Hormones Affect Agonist American Binding Biochemical Biological Assay Biology Cells Characteristics Chemicals Chronic Chronic inflammatory pain Clinical Trials Coupled Data Degenerative polyarthritis Development Diabetes Mellitus Docking Functional disorder G-Protein-Coupled Receptors Goals Human Hypersensitivity IL18 gene In Vitro Inflammasome Inflammation Inflammatory Ligands Link Macrophage Manuscripts Mechanics Mediating Metabolism Modeling Molecular Mus Nerve Neuropathy Non-Steroidal Anti-Inflammatory Agents Nuclear Proteins Nuclear Receptors Obesity Opioid Pain Physiological Physiological Processes Physiology Protein Isoforms Regulation Reproduction Research Research Personnel Research Project Grants Rewards Role Safety Site Stimulus Structure Techniques Testing Therapeutic Tissues Transcription Repressor addiction liability cell injury chronic pain chronic pain patient chronic painful condition cytokine design drug discovery efficacy evaluation efficacy testing in vivo inflammatory pain innovation mouse model nerve damage non-opioid analgesic novel pain symptom painful neuropathy pharmacologic pre-clinical receptor screening side effect small molecule targeted treatment therapeutic target tool transcription factor virtual screening

项目摘要

SUMMARY Chronic inflammation affects millions of Americans each year and can manifest in a variety of chronic pain conditions where normally innocuous stimuli produce pain symptoms. Long-term use of current pain therapeutics, including NSAIDS, corticosteroids, and opioids, can cause unwanted side effects, and addiction potential can limit their utilization. Recent studies have demonstrated a clear link between chronic low-grade inflammation and the increase in Chronic Inflammatory Pain (CIP) conditions. Alternative therapeutic targets are needed for the treatment of these painful conditions. Nuclear receptors, ligand-activated transcription factors that regulate a variety of physiological processes including metabolism, inflammation, reproduction, and development, represent key drug discovery targets (second to GPCRs). The REV-ERB proteins are nuclear receptors which function as transcriptional repressors and direct regulators of NLRP3 inflammasome components and proinflammatory cytokines (IL-1, IL-18), and regulate the activity of macrophages at sites of cellular damage. To date, the role of REV-ERB in relation to the manifestation of chronic pain symptoms has not been elucidated. Due to its role in NLRP3 inflammasome and proinflammatory cytokine regulation, we hypothesize that REV-ERB is a viable drug target for the treatment of inflammatory pain. Our strategy will leverage the known physiological functions of REV-ERB in chronic inflammation and use a chemical biology approach to identify novel REV-ERB ligands, with superior pharmacological profiles, to advance this potential therapy toward clinical trials. Our new preliminary data shows that total loss of REV-ERB in mice increases mechanical hypersensitivity. Our previous studies demonstrated that pharmacological activation of REV-ERB had no negative effects in preclinical mouse reward models, suggesting that targeting of REV-ERB may benefit many chronic pain conditions.

概括慢性炎症每年会影响数百万的美国人，并且可以体现在各种慢性Panin连接中通常，刺激性疼痛症状。皮质类固醇和阿片类药物可能会导致不良的副作用，而成瘾潜力可以限制其最近的利用。研究表明，慢性低级炎症与慢性炎症的增加之间存在明确的联系疼痛（CIP）条件需要替代治疗靶标。受体，配体激活的转录因子，这些因子是适当的各种生理过程，包括代谢，炎症，繁殖和发育代表关键的药物发现靶标（第二位于GPCR）蛋白质是核受体，可充当转录阻遏物和NLRP3炎症体的直接调节剂成分和促炎细胞因子（IL-1，IL-18），并调节细胞部位巨噬细胞的活性。迄今为止，Rev-erb在慢性疼痛症状的表现方面的作用尚未阐明。由于其作用Inlrp3炎性体和促炎细胞因子调节炎症疼痛的可行药物目标。慢性炎症中的Rev-erb，并使用化学生物学来识别以识别Rev-erb配体，并具有优越性的我们的新临床临床试验。小鼠的Rev-erb损失提高了我们先前的研究。 Rev-ERB的激活在临床前小鼠奖励模型中没有负面影响，这表明对Rev-erb的靶向可能会使许多慢性疼痛状况受益。