We have discovered a new way of discovering and developing retinoid-based drugs that show considerable potential for the treatment of Alzheimer’s disease (1) and amyotrophic lateral sclerosis (2). These drugs work on the retinoic acid receptor class of nuclear receptors and, crucially, also on a new, mostly-unexplored, retinoid target. These drugs have powerful effects to improve neuronal survival and increase the capacity of neurons to send out neurites. Thus the drugs have the possibility of treating a range of neurodegenerative diseases.
Our group is one of the world-leaders in understanding the function of retinoic acid in the brain (3). The project will further develop the drug discovery methods with a focus on the mechanisms by which retinoic acid receptors act, both through a genomic response to activate gene transcription and a rapid non-genomic action, which involves kinase activation.
Working in concert with chemistry partners, who will be designing new drugs based upon the results provided by the student, studies to identify, optimise and understand these drugs will be conducted. These will first use in vitro methods including cell lines and primary neural cells and finally disease model animals. The techniques employed will 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.
The project is highly interdisciplinary and involves a large and diverse consortium of researchers, based at a number of different Universities, and a number of industrial partners, allowing all aspects of fundamental and translational science to be addressed, and familiarity with a broad spectrum of subject matter to be obtained. The student will work with new RAR activator drugs designed by Professor Whiting, a co-supervisor of the project, at Durham University. Working with Professor Whiting, the shape and properties of the designed drugs will be correlated with their ability to promote bioactivity and neuronal survivability. Part of the research will involve collaboration with industry to help commercialize future drugs.
From this project, the student will be 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.
1. Chakrabarti M, McDonald AJ, Will Reed J, Moss MA, Das BC, Ray SK. Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer's Disease. J Alzheimers Dis. 2016;50:335-52
2. Riancho J, Ruiz-Soto M, Berciano MT, Berciano J, Lafarga M. Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis. Front Cell Neurosci. 2015 Jul 1;9:250
3. Shearer KD, Stoney PN, Morgan PJ, McCaffery PJ. A vitamin for the brain. Trends Neurosci. 2012;35:733-41