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

项目摘要(最多4000个字符，包括空格/回车)-从最初的提案来看，衰老的特征是神经肌肉功能和肌肉质量/力量的丧失，这导致虚弱和生活质量下降。这给英国医疗保健以及全球造成了巨大的社会经济负担。维甲酸(RA)信号已成为神经肌肉修复/再生的重要调节因子。它的大部分作用是通过与RA反应元件(RARE)结合来调节靶基因的核内RA受体(RARa/b/y)以及通过非基因组途径实现的。活性维生素A，维甲酸(RA)，已被认为对神经肌肉功能有深远的影响。然而，临床使用的维生素A代谢物的主要缺点之一是半衰期短和光不稳定。我们的中小企业合作伙伴nevargenics已经开发出一种双作用合成维甲酸的面板，具有更高的效力和更高的光稳定性。此外，监督小组最近使用外周运动神经元模型(Durham)和肌肉细胞分化的时间效应(利物浦)表征了一些先导化合物。昼夜节律调节体内的许多生理过程，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，最佳的昼夜节律时机是药物成功的一个重要决定因素--它可以将耐受性提高多达10倍，并使&gt；500药物的疗效提高一倍。85%的半衰期和15小时的药物表现出一天中的时间依赖性，大多数合成维甲酸的半衰期短到中等。然而，维甲酸铅给药方案的最佳剂量和时间尚未确定，以提高药物疗效并避免不良副作用。本项目将研究以下假设：1)骨骼肌和运动神经元细胞显示出RA信号的昼夜节律性调节，这种调节随着年龄的变化而改变；2)按时间安排的维甲酸给药改善了RA信号靶点的参与；3)随着年龄的增加，神经肌肉的变化可以通过按时间安排的维甲酸治疗部分恢复。本研究的主要目的如下：1.确定幼年和老年动物骨骼肌和运动神经元中RA信号的昼夜节律。2.利用时钟报告细胞和组织块表征时间安排的维甲酸处理的效果。研究有时间安排的维甲酸对与年龄相关的神经肌肉变化的影响，以及生物钟和RA信号之间的模型相互作用，以预测它们之间的相互作用。在这个博士项目中，我们将收集必要的概念验证数据，以确定内生学先导维甲酸的最佳时机，这将形成一个框架，在神经肌肉老化的活体模型和维甲酸效应的电子模型中进行药物测试。

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.