Targeting muscarinic receptors in treating and slowing the progression of neurodegeneration
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
Studentship strategic priority area: Industrial collaborative research
Keywords: Muscarinic, neurodegeneration, electrophysiology, GPCR, Drug discovery
Current treatments for memory loss in Alzheimer's disease (AD) have limited clinical benefit and show significant side effects. There are also no treatments that can cure or slow AD. Working with the drug company, Eli Lilly, we have recently demonstrated that novel ligands acting on M1 muscarinic receptors in the brain can reverse memory loss and slow disease progression in a mouse model of neurodegeneration. This PhD will aim to contribute to the development of these drugs by asking - which brain neuronal networks are acted on by these novel compounds and how do they change neuronal activity in neurodegenerative disease?
Project:
The objectives of this PhD will be met by measuring brain activity and neuronal circuitry in live mice using in vivo electrophysiology. Through collaboration with our industrial partners Eli Lilly the student will learn this approach in a one-year placement at Lilly. The student will then transfer the technology to John Riddell's laboratory who in collaboration with the Bradley/Tobin laboratories will marry this approach with novel genetically engineered mice together with a panel of M1 and M4-muscarinic receptor ligands to determine the neuronal networks acted on by muscarinic drugs.
The project has of three components:
1. Determination of neuronal network responses in live mice following muscarinic receptor drug administration. The student will learn in vivo electrophysiology techniques for neuronal recording activity via multichannel electrodes chronically implanted in the brain. Cutting edge technology for wireless transmission of these recordings from a miniaturised device will allow monitoring of this activity in awake, freely moving animals during cognitive behavioural tasks. This will be carried out under the supervision of Dr. Keith Phillips at the Eli Lilly laboratories (UK).
2. Determination of changes in neuronal network activity during neurodegenerative disease. In year two the student, with the help of Lilly scientists, will transfer the electrophysiology technology to Glasgow where the student will use the mouse prion model of neurodegeneration established in the Bradley/Tobin labs to evaluate changes in neuronal circuitry during prion disease.
3. Determination of how muscarinic receptor drugs impact on neuronal networks during neurodegeneration. The final objective will investigate the effects of muscarinic receptor ligands on neuronal circuits in prion diseased mice.
Keywords: Muscarinic, neurodegeneration, electrophysiology, GPCR, Drug discovery
Current treatments for memory loss in Alzheimer's disease (AD) have limited clinical benefit and show significant side effects. There are also no treatments that can cure or slow AD. Working with the drug company, Eli Lilly, we have recently demonstrated that novel ligands acting on M1 muscarinic receptors in the brain can reverse memory loss and slow disease progression in a mouse model of neurodegeneration. This PhD will aim to contribute to the development of these drugs by asking - which brain neuronal networks are acted on by these novel compounds and how do they change neuronal activity in neurodegenerative disease?
Project:
The objectives of this PhD will be met by measuring brain activity and neuronal circuitry in live mice using in vivo electrophysiology. Through collaboration with our industrial partners Eli Lilly the student will learn this approach in a one-year placement at Lilly. The student will then transfer the technology to John Riddell's laboratory who in collaboration with the Bradley/Tobin laboratories will marry this approach with novel genetically engineered mice together with a panel of M1 and M4-muscarinic receptor ligands to determine the neuronal networks acted on by muscarinic drugs.
The project has of three components:
1. Determination of neuronal network responses in live mice following muscarinic receptor drug administration. The student will learn in vivo electrophysiology techniques for neuronal recording activity via multichannel electrodes chronically implanted in the brain. Cutting edge technology for wireless transmission of these recordings from a miniaturised device will allow monitoring of this activity in awake, freely moving animals during cognitive behavioural tasks. This will be carried out under the supervision of Dr. Keith Phillips at the Eli Lilly laboratories (UK).
2. Determination of changes in neuronal network activity during neurodegenerative disease. In year two the student, with the help of Lilly scientists, will transfer the electrophysiology technology to Glasgow where the student will use the mouse prion model of neurodegeneration established in the Bradley/Tobin labs to evaluate changes in neuronal circuitry during prion disease.
3. Determination of how muscarinic receptor drugs impact on neuronal networks during neurodegeneration. The final objective will investigate the effects of muscarinic receptor ligands on neuronal circuits in prion diseased mice.
People |
ORCID iD |
| Sophie Bradley (Primary Supervisor) | |
| Jessica Bowden (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R01566X/1 | 01/10/2018 | 30/09/2025 | |||
| 2127089 | Studentship | MR/R01566X/1 | 10/09/2018 | 10/03/2022 | Jessica Bowden |