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Megan Holmes

Profile

on
Title: 
Prof
Megan
Holmes
Admin unit: 
Endocrinology
Job title: 
Professor of Molecular Neuroendocrinology
Contact email: 
Megan.Holmes@ed.ac.uk
Telephone: 
242 6737
Room: 
C3.10
Location: 
QMRI
Address: 
47 Little France Crescent

Research

Background: 

Glucocorticoids have many actions within the body, but it is their actions within the brain and the how the brain controls glucocorticoid release that has been the main focus of my research. It is crucial to tightly regulate glucocorticoid levels to prevent hyperglycemia, insulin resistance, obesity, hypertension, metabolic syndrome, and mood disorders such as depression.

Early-life programming and 11ß-HSD2

The glucocorticoid metabolising enzyme, 11ß-HSD2, converts active cortisol/corticosterone to inactive cortisone/11-dehydrocortisosterone. It is highly expressed in the placenta where it is hypothesized to protect the developing fetus from high levels of glucocorticoids which will alter cell proliferation, differentiation and developmental timings. This will generate long-term consequences on the offspring, making them more susceptible to diseases in later life, such as metabolic syndrome, hypertension and mood disorders.

Consistent with this hypothesis, mice lacking 11ß-HSD2 are born smaller, have delayed postnatal development and exhibit abnormal anxiety behaviour as adults (have decreased entries into more anxiogenic open arm of the Elevated –plus maze). Furthermore, placentas from HSD2-/- mice are smaller, are less vascularized and are dysfunctional, delivering less nutrients to the fetus. Hence, a novel hypothesis is that HSD2 is there to protect the placenta rather than the fetus from high maternal glucocorticoids.

So the question is: Which is the most important site of HSD2 protection against adverse prenatal glucocorticoid programming – the placenta or the fetus? Or both?  To answer this question, we have generated brain-specific and placental-specific HSD2 knockout mice.This will enable us to determine the role of HSD2 in cardio-metabolic programming as well as programming of behaviour.

Early life challenges and life-long risk

Early-life challenges have been implicated in many diseases including cardio-metabolic and psychiatric diseases, such as schizophrenia and depression. Furthermore, the life-long allostatic load will tip the system from healthy ageing into dementias. In our studies we are investigating the interaction of glucocorticoid environment with genetic susceptibility and development to understand the mechanisms causal to adverse ageing. 

Alongside the measurement of physiological parameters (eg blood pressure, metabolism), behavioural assessments (cognitive and mood) and gene expression, we are using imaging paradigms to determine  longitudinal changes, particularly in the brain that may underpin the adverse outcomes.

We (in collaboration with Ian Marshall, Jeremy Hall and others) have set up conscious rat fMRI to study network activation in respose to a learnt fear conditioned cue. This enables us to assess the extent and pattern of activation while the rat is carrying out a simple cognitive task. We can then asess any modulations of this activation in response to early-life challenges and drug treatments.


 

 

 

 

Responsibilities: 

I run my own research group withing the CVS, am a member of the CVS senior advisory board, and member of the Seminar and symposium committee of the CVS. I am a Fellow of the Society for Biology, a member of Faculty F1000 Biology. I am treasurer of the British Society for Neuroendocrinolgy. I am Associate Editor of Stress and am on the Editorial Board of the Journal of Neuroendocrinology.

Research images: 
BOLD Activation in Lateral Amygdala in response to Conditioned stimulus

Grants

Funding body Principal grant holder Title Start date End date Amount
1 Medical Research Council Karen Chapman Glucocorticoid Receptor in the Early Life Programming of Cardiac Resiliance 01/09/2016 31/08/2019 463116
2 British Society for Neuroendocrinology Megan Holmes Studentship award (Manu Verma) 01/12/2014 30/11/2015 5000
3 British Society for Neuroendocrinology Megan Holmes Support Grant for PhD Studentship : Sandra Crombie 01/08/2013 31/07/2014 5000
4 Abott Laboratories Megan Holmes Development and disease of biomarkers for neuroscience indications: Functional analysis of affective and cognitive processing in awake rodents. 23/12/2011 22/12/2013 184418
5 Abbott Laboratories Megan Holmes Development and disease of biomarkers for neuroscience indications: Functional analysis of affective and cognitive processing in awake rodents - Supplement award 01/09/2011 20/12/2014 11031
6 Society for Endocrinology Megan Holmes Summer Studentship 2009 01/07/2009 08/09/2009 2770
7 TMRI - Wyeth Ian Marshall Conscious animal fMRI 01/10/2008 31/03/2010 302460
8 Wellcome Trust Megan Holmes Functional importance of RNA editing of the 5-HT2C receptor in vivo using a gene-targeting approach 01/03/2007 28/02/2011 364554
9 Wellcome Trust Megan Holmes Prenatal programming of anxiety behaviour by glucocorticoids: A function of 11BHSD2 activity in the brain or placenta or both? 01/04/2006 31/03/2010 462653
10 MRC Tony Harmar The control of peripheral circadian rhythms 01/01/2004 01/01/2009 1080000