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Investigating associations between the brain renin angiotensin system and Traumatic Brain Injury


Bristol Medical School

About the Project

Rationale
In the last decade the involvement of the brain Renin Angiotensin System (RAS) in neurodegenerative disease, particularly Alzheimer’s disease (AD) has come to the fore. Part of this involvement is evidence of how imbalance in RAS may give rise to and exacerbate tau pathology. Effective management of or mitigation against risk factors may be one of the most effective ways of reducing rates of AD and other dementias. One often overlooked risk factor is traumatic brain injury (TBI), which can be caused by blunt or repetitive traumas, perhaps because opportunities for its prevention may be limited, although the long-term effects might be mitigated against with timely intervention. One form of TBI that has rose to prominence in relation to several forms of profession sports is that which gives rise to chronic traumatic encephalopathy (CTE). This is a progressive degenerative disease found in people who have had a severe blow or repeated blows to the head seen in a number of professional, contact or extreme sports; certain social/entertainment-based activities; and domestic violence, where repeated concussions or other brain trauma occur. Importantly, CTE is classified as a ‘tauopathy’, which means it presents with pathology associated with tau protein that is also involved in AD and some other dementias and thus there is now a timely need to explore the extent to which RAS imbalance seen in relation to AD pathology might similarly contribute to CTE pathology and severity.

Aims & Objectives
We have the knowledge and expertise to train a student to design and execute studies to investigate the RAS imbalance in post-mortem brain tissue where we wish to undertake the first investigations of its kind in relation to the neuropathology of CTE. The investigations will be towards gathering information on the extent of RAS activation in relation to CTE Pathology to inform the potential for RAS-acting drugs as possible acutely administered drugs in the event of a TBI.

The following are examples (but not a limited list) of specific hypotheses that we wish to test:
1. To what extent does RAS activation occur in CTE and in relation to CTE neuropathology.
2. What is the extent of imbalance between destructive and protective elements of the RAS in CTE.

Methods
There are multiple potential projects possible in this topic area and where following consultation 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 one or more brain regions) from diseased and non-diseased persons. These may then be extended to include complementary studies designed and executed in other laboratory experimental systems (in vitro or cell-culture based), ex vivo (in other experimental models or more human tissue sources from patients) 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 part of their initial training and input into their projects.

References

Kehoe PG. The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment? J Alzheimers Dis. 2018;62(3):1443-66.

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.

Villapol S et al. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 2015; 138(11):3299-3315.

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