Rethinking the retinoic acid receptor: a revisionary view of the rapid pathways triggered
Lead Research Organisation:
University of Aberdeen
Department Name: Sch of Medicine, Medical Sci & Nutrition
Abstract
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
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
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T00875X/1 | 01/10/2020 | 30/09/2028 | |||
| 2281971 | Studentship | BB/T00875X/1 | 01/10/2021 | 30/09/2025 |