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）-来自原始提案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。这对英国医疗保健以及全球构成了重大的社会经济负担。视黄酸（RA）信号传导最近已成为神经肌肉修复/再生的重要调节剂。其主要作用是通过核内RA受体（RAR a/B/y）与RA反应元件（RAREs）结合调节靶基因和通过非基因组途径介导的。活性维生素A，视黄酸（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它们的半衰期短和光不稳定。我们的SME合作伙伴Nevrargenics开发了一系列双作用合成类维生素A，具有更高的效力和更高的光稳定性。此外，监管团队最近使用外周运动神经元模型（达勒姆）和对肌细胞分化的时间效应（利物浦）表征了一些先导化合物。昼夜节律定时调节体内的许多生理过程，包括信号通路和药物代谢的及时激活。临床前和临床数据表明，最佳昼夜节律时间是药物成功的重要决定因素-它可以将耐受性程度提高10倍，并使>500种药物的疗效程度提高一倍。>85%的半衰期<15小时的药物表现出时间依赖性，大多数合成类维生素A具有短至中等的半衰期。然而，先导类维生素A的最佳剂量和给药方案的时机尚未制定，以提高药物疗效和避免不良副作用。 该项目将研究以下假设：1）骨骼肌和运动神经元细胞显示RA信号的昼夜调节，其随年龄而改变; 2）时间安排的类维生素A给药可改善RA信号靶点参与; 3）使用时间安排的类维生素A治疗可部分挽救随年龄的神经肌肉变化。该项目有以下主要目标：1.确定年轻和老年动物骨骼肌和运动神经元中RA信号传导的昼夜调节。2.使用时钟报告细胞和组织细胞表征按时间安排的类维生素A治疗的效果。研究时间安排的维甲酸对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，我们将收集关于Nevrargenics导致维甲酸的最佳时间的基本概念验证数据，这将形成一个框架，用于在神经肌肉老化的体内模型中进行药物测试和维甲酸效应的计算机建模。

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.