Rethinking the retinoic acid receptor: a revisionary view of the rapid pathways triggered

对药物/靶点相互作用的完整了解对于开发以所需方式触发其受体的有效药物至关重要。例如，核受体的主要作用是控制基因表达，而筛选转录控制是识别将被开发为药物的受体配体的典型第一步。核受体是许多最常用的处方药的靶标。然而，这忽略了这些受体的一个主要作用，即快速控制“非基因组”功能，例如，与激酶活性相互作用和调节。这个项目将专注于理解和确定这些快速的非基因组作用对一种在许多细胞功能中至关重要的受体--维甲酸受体的相对重要性。这些受体的非基因组功能还很少被探索，但对这些途径的全面研究将在未来开辟新的途径，将其用作治疗包括阿尔茨海默病和肌萎缩侧索硬化症在内的神经退行性疾病的药物。这个学生项目是世界领先的合作伙伴，在为维甲酸受体设计新的配体方面，在杜伦大学，在阿伯丁大学，在维甲酸功能的神经生物学方面。在达勒姆大学化学系，这名学生将与怀廷教授合作长达18个月，研究新设计的维甲酸受体配体的形状、分子特性和受体亲和力，并在设计中使用新的数学建模工具。与阿伯丁的麦卡弗里教授合作，这将与它们在神经细胞中的生物活性以及它们促进神经元存活的能力相关联。生物结果将反馈，以进一步提炼和优化配体的化学设计。因此，这个项目是高度跨学科的，学生将被教授各种各样的技术，包括各种维甲酸活动的生物测定，包括转录活动，通过各种激酶的非基因组信号以及翻译的控制。维甲酸受体(RARs和RXRs)的功能将通过siRNA和CRISPR/Cas9基因敲除以及转基因动物模型等方法进行深入研究。作为案例学生，在达勒姆的工作将与“nevrargenics Ltd.”公司合作，怀廷教授是该公司的首席执行官。因此，学生将体验到药物设计中涉及的基础科学和转化科学的方方面面。在阿伯丁，学生还将与nevargenics的首席技术官Greig博士合作，因此，这些研究将继续是nevargenics在药物开发工作中不可或缺的一部分。总而言之，这个学生项目将使学生熟悉研究和操作受体蛋白质的技术，将学习药物发现的方法，并帮助开发新一代药物。这些研究的最终目的将是确定选择性靶向视黄酸受体系统的效果，并最终开发选择性药物，使我们能够提高该系统对神经退行性疾病，特别是阿尔茨海默病和肌萎缩侧索硬化症的治疗潜力。

Complete understanding of drug/target interaction is essential to develop effective drugs that trigger their receptor in a desired way. For instance, the primary action of nuclear receptors, targets for many of the most frequently prescribed drugs, is control of gene expression and screening for control of transcription is the typical first step of identifying the receptor ligand that will be developed into a drug. However, this misses a major action of these receptors to rapidly control "non-genomic" functions to, for instance, interact with and regulate kinase activity. This project will focus on understanding, and determining the relative importance of these rapid non-genomic actions for a receptor that is important in many cellular functions, the retinoic acid receptor. The non-genomic function of these receptors has been little explored but a comprehensive study of these pathways has the future impact of opening new ways to use these as drugs directed in the future to neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis.This studentship project is collaborative between world leaders in design of novel ligands for the retinoic acid receptors, based at Durham University, and in the neurobiology of retinoic acid function, at the University of Aberdeen. In the Department of Chemistry at Durham University the student will work for up to 18 months with Professor Whiting on the shape, molecular properties and receptor affinities of newly designed retinoic acid receptor ligands employing novel mathematical modelling tools in this design. This will be correlated, working with Professor McCaffery in Aberdeen, with their bioactivity in neural cells and their ability to promote neuronal survivability. The biological results will feedback to further refine and optimise chemical design of the ligands. Thus, the project is highly interdisciplinary and the student will be taught a wide variety of techniques that include a variety of bioassays for retinoid activity including transcriptional activity, non-genomic signalling via a variety of kinases as well as control of translation. The function of the retinoic acid receptors (RARs and RXRs) will be studied in-depth by methods including siRNA and CRISPR/Cas9 knockdown as well as transgenic animal models.As a CASE studentship, the work performed in Durham will be with the company "Nevrargenics Ltd.", for which Professor Whiting is CEO. The student will thus experience all aspects of fundamental and translational science to be addressed in drug design. In Aberdeen the student will also work with Dr. Greig, CTO of Nevrargenics, and thus the studies will continue to be integral to Nevrargenics' work in drug development.In summary, this studentship project will enable the student to become familiar with techniques to study and manipulate receptor proteins, will have learned methods in drug discovery and helped develop a new generation of drugs. The ultimate aim of these studies will be to determine the effects of selective targeting of the retinoic acid receptor system, and eventual development of selective drugs which will allow us to improve the therapeutic potential of this system for neurodegenerative disease, in particular Alzheimer's disease and amyotrophic lateral sclerosis