Targeting Neuromuscular Ageing using Novel Synthetic Retinoids and Chrono-pharmacological Approaches

使用新型合成类维生素A和时间药理学方法对抗神经肌肉衰老

• 批准号: 2888421
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2888421
• 关键词: Targeting; Neuromuscular; Ageing; using; Novel

Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Ageing is characterized by a loss of neuromuscular function and muscle mass/strength, which contributes to frailty and lower quality of life. This poses a significant socio-economic burden on the UK healthcare as well as globally. Retinoic acid (RA) signalling has recently emerged as an important regulator of neuromuscular repair/regeneration. Most of its effects are mediated by nuclear RA receptors (RAR a/b/y) through binding to RA-responsive elements (RAREs) to regulate target genes and through non-genomic pathways. Active vitamin A, retinoic acid (RA), has been known to have profound effects on neuromuscular function. However, one of the main drawbacks of vitamin A metabolites for clinical use is their short half-life and photic instability. Our SME partner, Nevrargenics, has developed a panel of dual-acting synthetic retinoids with improved potency and increased light stability. In addition, supervisory team has recently characterised some of the lead compounds using peripheral motor neuron models (Durham) and time-of-day effects on muscle cell differentiation (Liverpool). Circadian timing regulates many physiological processes in the body, including timely activation of signalling pathways and drug metabolism. Preclinical and clinical data show that optimal circadian timing is an important determinant of drug success-it modifies up to tenfold the extent of tolerability and doubles the extent of efficacy for >500 drugs. >85% of drugs with half-lives <15hrs show time-of-day dependency, and most synthetic retinoids have short to moderate half-lives. However, the optimal dose and timing of administration regimens of lead retinoids is yet to be formulated to improve drug efficacy and avoid undesirable side effects. This project will investigate the following hypotheses that: 1) skeletal muscle and motor neuron cells show circadian regulation of RA signaling, which is altered with age and 2) Time-scheduled retinoid administration improves RA signaling target engagement and 3) Neuromuscular changes with age can be partially rescued using time-scheduled retinoid treatments. This project has the following main aims:1. Determine the circadian regulation of RA signalling in skeletal muscle and motor neurons from young and old animals. 2. Characterize the effects of time-scheduled retinoid treatments using clock reporter cells and tissue explants.3. Investigate the effect of time-scheduled retinoids on age-related neuromuscular changes and model interactions between circadian clocks and RA signaling to predict their mutual interactions.In this PhD project we will gather essential proof-of-concept data as to the optimal timing of Nevrargenics lead retinoids, which will form a framework for drug testing in in vivo models of neuromuscular ageing and in silico modelling of retinoid effects.

项目摘要（最多有4000个字符，包括空间/收益） - 从原始提案老化的特征是神经肌肉功能和肌肉质量/力量的丧失，这有助于脆弱和较低的生活质量。这给英国医疗保健以及全球带来了重大的社会经济负担。视黄酸（RA）信号最近已成为神经肌肉修复/再生的重要调节剂。它的大部分作用是由核RA受体（RAR A/B/Y）与RA反应元件（RARES）结合来介导的，以调节靶基因和非基因组途径。活跃的维生素A，视黄酸（RA）已知对神经肌肉功能具有深远的影响。然而，维生素A代谢物的主要缺点之一是它们的半衰期和光子不稳定性。我们的中小型企业伴侣Nevranics已开发了一组双作用合成类维生素，具有提高效力并提高了光稳定性。此外，监督团队最近使用外围运动神经元模型（Durham）和对肌肉细胞分化的时间影响（利物浦）表征了一些铅化合物。昼夜节律定时调节体内许多生理过程，包括及时激活信号通路和药物代谢。临床前和临床数据表明，最佳的昼夜节律是药物成功的重要决定因素 - 它可以修改耐受性的程度，并使> 500种药物的疗效程度增加了一倍。 > 85％的半衰期<15小时的药物显示出时间的依赖性，并且大多数合成性类动物的半衰期短至中度。然而，尚未制定铅类维生素类动物的最佳剂量和时间安排，以提高药物疗效并避免不良的副作用。 该项目将调查以下假设：1）骨骼肌和运动神经元细胞显示RA信号传导的昼夜节律调节，随着年龄的增长和2）时间安排的类维生素类动物的给药可改善RA信号的目标参与，3）3）神经肌肉变化，随着年龄的增长而变化。使用时间表的视网膜类似治疗部分被部分救出。该项目具有以下主要目的：1。确定来自年轻动物和老动物的骨骼肌和运动神经元中RA信号传导的昼夜节律调节。 2。表征使用时钟记者细胞和组织外植体的时间扫描类视黄素处理的影响3。研究时间策划的类视黄素对年龄相关的神经肌肉变化的影响以及昼夜节律和RA信号之间的模型相互作用以预测其相互作用。在这个博士学位项目中，我们将收集有关Nevrargenics最佳时机的基本概念证明数据铅类维生素类动物将在神经肌肉衰老的体内模型和类维生素类动物效应的计算机模型中形成药物测试的框架。