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

重新思考视黄酸受体：对触发的快速途径的修正观点

• 批准号: 2281971
• 金额: --
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2281971
• 关键词: Rethinking; retinoic; acid; receptor; revisionary

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

完全了解药物/靶标相互作用对于开发有效的药物，以期望的方式触发其受体。例如，核受体的主要作用是许多最常见的药物的靶标，是控制基因表达和控制转录的筛查是识别将发展为药物的受体配体的典型第一步。但是，这错过了这些受体的重大作用，以快速控制“非基因组”功能，例如与激酶活性相互作用并调节激酶活性。该项目将集中于理解，并确定这些快速非基因组作用对受体的相对重要性，这在许多细胞功能（视黄酸受体）中很重要。 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视黄酸功能的神经生物学，阿伯丁大学。在达勒姆大学化学系中，该学生将在新设计的视黄酸受体配体的形状，分子特性和受体亲和力上工作长达18个月，并采用这种设计中的新数学建模工具。这将与阿伯丁的麦卡菲教授合作，与它们在神经细胞中的生物活性及其促进神经元生存能力的能力相关。生物学结果将反馈以进一步完善和优化配体的化学设计。因此，该项目是高度跨学科的，将教授学生多种技术，其中包括各种生物测定视网膜类似活动的生物测定，包括转录活性，通过多种激酶以及翻译的控制，包括转录活性，非基因组信号传导。视黄酸受体（RARS和RXR）的功能将通过包括siRNA和CRISPR/CAS9敲低以及转基因动物模型在内的方法进行深入研究。作为案例学生，达勒姆（Durham）进行的工作将与“ Nevrargenics Ltd.”公司（Nevrargenics Ltd.）进行。因此，学生将体验在药物设计中要解决的基本和转化科学的各个方面。在阿伯丁中，学生还将与Nevrangics CTO的Greig博士合作，因此，这些研究将继续是Nevrangenics在药物开发中的工作不可或缺的一部分。总而言之，该学生训练项目将使该学生能够熟悉研究和操纵受体蛋白的技术，从而在药物发现中学习了药物发现和开发新一代药物。这些研究的最终目的是确定视黄酸受体系统的选择性靶向的影响，以及最终开发选择性药物，这将使我们能够改善该系统对神经退行性疾病的治疗潜力