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Studies of brain renin angiotensin system changes in Parkinson’s disease to find new treatments


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Rationale
Parkinson’s disease (PD) is the second most common forms of neurodegenerative disease and affects people from the ages of 50years and above. Currently PD has no cure and has only a limited number of symptomatic treatments that have a short duration of effect due to the progressive nature of the underlying pathology. There remains urgent need for disease-modifying and neuroprotective therapies.

The brain Renin Angiotensin System (RAS) has emerged as a likely pathway that may be implicated in PD, based on similarities between Alzheimer’s disease (AD) and PD and where RAS has been found to be significantly involved. There is already some supportive evidence of RAS involvement in PD related to observed neuroprotective effects of RAS-acting drugs in various preclinical models of PD and observational clinical studies of PD patients. However, there remains a translational gap in our knowledge between the supportive evidence from various pre-clinical models and observational studies of patient population that warrants filling through a more comprehensive examination of the activities of key components of RAS activity in the PD brain. These are needed not only to validate observations in preclinical models, but also guide the refinement of what might be the most effective therapeutic approaches that could arise from RAS-acting drug classes that might be testable in PD patients in future clinical trials.

Aims & Objectives
We have the knowledge and expertise to train a student to design and execute studies to investigate the RAS in relation to PD and its associated neuropathology. Our studies are always directed towards long term translational aims that will hopefully benefit patients in the future. Thus the research we undertake has the potential to inform the identification of new mechanisms and/or treatments that would form the basis of tackling the complex multifaceted aspects of Parkinson’s disease, whilst also continuing to inform the emerging but still incomplete story of the role of the RAS in the brain itself and its role in the neurobiology of the brain. The following specific research questions will be addressed:

1. To investigate changes in the central brain RAS pathway in post-mortem brain tissue from PD patients and non-affected controls in relation to markers of disease pathology (e.g. alpha-synuclein level, neuronal loss).
2. To examine the extent to which imbalance between the classical and counter-regulatory axes of the RAS exist in Parkinson’s disease.
3. To compare changes in frontal lobe changes in RAS in PD and AD.


Methods
There are multiple potential projects available in this new area of research for the group and where following consultation with students we would design a suite of methodological approaches to investigate the agreed research questions. Ordinarily most studies commence with foundation experiments (using molecular genetic, biochemical, immunohistochemical and/or histological approaches) in carefully selected post-mortem brain tissue from diseased and non-diseased persons. These are then usually extended to include complementary studies designed and executed in other laboratory experimental systems (in vitro or cell-culture based), ex vivo (in disease models or more human tissue sources) or in vivo in small pre-clinical trials (time and resources permitting). Projects are intentionally not prescriptive at this stage as we seek to give PhD students the opportunity to develop and design projects with us from the outset as parts of their initial training and input into their projects.

References

Perez-Lloret S et al. Renin-angiotensin system as a potential target for new therapeutic approaches in Parkinson's disease. Expert Opin Investig Drugs. 2017;26(10):1163-73.

Kehoe PG et al. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-beta and tau pathology. Alzheimers Res Ther. 2016;8(1):50.


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