UK Dementia Research Institute at Imperial College London - Seminar Series

30 January 2019

 Epigenetic mechanisms in Alzheimer’s disease

Katie LunnonGuest lecture - Wednesday 30 January 2019
Dr Katie Lunnon
Associate Professor in Epigenetics
University of Exeter Medical School

Biography

Katie is an Associate Professor in Epigenetics at the University of Exeter Medical School, with a particular interest in dementia. Her group published the first genome-wide, cross-tissue epigenome-wide association study (EWAS) in Alzheimer’s disease (AD) (Lunnon et al, Nat Neurosci-2014), which has been cited >200 times. This year her group published a follow up EWAS paper highlighting differential DNA methylation across an extended 48kb region in the HOXA3 gene in individuals with AD (Smith et al, Alzheimers Dement-2018). Katie currently leads a team of three postdoctoral researchers and five postgraduate students, who are utilising a range of cutting-edge methodologies to elucidate the role of epigenetic mechanisms in dementia. They are using sophisticated bioinformatics approaches to meta-analyse all available AD EWAS datasets and also perform integrative multi-omics analyses in well characterised cohorts to combine different levels of molecular information. They are also performing a range of wet lab molecular and cellular biology experiments, including epigenetic editing in induced pluripotent stem cells (iPSCs).

Katie was recently awarded the Alzheimer’s Research UK Young Investigator of the Year award in 2017 and an Alzheimer’s Society Dementia Research Leaders award in 2015 for academic achievements.  Katie is module lead for the final year double (30) credit module "Frontiers in Neuroscience" on the BSc Medical Sciences program, co-ordinator of the Alzheimer’s Research UK South West Network Centre and sits on the ARUK grant review board.

Host

Professor Paul Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@Imperial.ac.uk) to arrange to meet with the speaker

Date and time

Wednesday 30 January 2019
12:30 - 13:30
Light lunch available from 12:00 in the Wolfson Cafe

Venue

Wolfson Education Centre
Hammersmith Campus

Directions to the Hammersmith Campus and campus map are available on the College 'visit Hammersmith' web page

5 February 2019

Prof Valerie O'DonnellGuest lecture - 5 February
Professor Valerie O’Donnell 
Director, Division of Infection and Immunity & Co-Director of Systems Immunity Research Institute,
Cardiff University
 

Biography

Valerie O’Donnell is currently Director of Division of Infection and Immunity at Cardiff University, and Co-Director of Systems Immunity Research Institute which she co-founded in 2016 (£4.2M).  She is Strategic Management lead of the LIPID MAPS Gateway (www.lipidmaps.org) which is a Wellcome Trust funded bioresource, joint led with UCSD and Babraham, and with over 1M users annually.  She supervises an interdisciplinary group of scientists with biomedical, clinical and physical sciences backgrounds.  She is an ERC Advanced Investigator and lipid biochemist whose research is focused on using mass spectrometry for discovery and characterization of new lipid mediators of inflammation.  For the last 10 yrs she has studied how specialized lipids generated by circulating vascular cells regulate inflammation, wound healing and thrombosis.  She particularly focused on around 150 molecular species of lipids termed enzymatically-oxidized phospholipids (eoxPL) made by platelets, neutrophils, monocytes and eosinophils. They were discovered, characterized and chemically synthesized in her group, and then analyzed in vitro and in vivo in human clinical samples and mouse models, for their biological and pathophysiological actions.  In collaboration with Collins and Krönke, she showed that they are essential for normal blood clotting, and conversely are elevated in thrombotic disease (1-3). The detailed biochemical and biophysical mechanisms of action were elucidated.  Valerie also showed they regulate neutrophil antibacterial actions and transcriptional activation in monocytes. With Conrad, a key role for eoxPL in a cell death pathway, ferroptosis, was found (4). eoxPL are an essential part of the healthy innate immune system, however when inappropriately generated in the blood stream or in excess, they contribute directly to vascular inflammation.   

1.     Lauder, SN et al (2017) Networks of enzymatically oxidized membrane lipids support calcium - dependent coagulation factor binding to maintain hemostasis. Science Signaling Vol. 10, Issue 507, eaan2787, DOI: 10.1126/scisignal.aan2787

2.     Uderhardt et al (2017) Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis and thrombotic disease  J Exp Med 214(7):2121-2138. doi: 10.1084/jem.20161070

3.     Slatter et al (2016) Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metabolism 23, 930-934, with commentary by FitzGerald, GA, Human platelet lipidomics: variance, visualization, flux and fuel.  23, 757-759

4.     Friedmann Angeli et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology (DOI: 10.1038/ncb3064) 16, 1180–1191 [IF 20.7]

Abstract

Enzymatically-oxidized phospholipids (eoxPL) are generated through regulated processes, by attaching eicosanoids or prostaglandins to phospholipids (PL) in immune cells, following acute agonist activation. These lipids comprise structurally diverse families of biomolecules, and it is becoming increasingly clear that they possess significant immunoregulatory roles in both health and disease. The idea that oxidized PL (oxPL) can form via enzymatic pathways and signal biologically in their own right has only recently been realized. eoxPL form through the co-ordinated actions of cellular lipoxygenases, cyclooxygenases, and Land’s cycle enzymes. They display emerging roles in cellular events that include ferroptosis, apoptosis and blood clotting, and diseases such as arthritis, diabetes and cardiovascular disease. In our lab, we used several mass spectrometry approaches (precursor scanning, untargeted) to map eoxPL in human blood cells, including platelets, neutrophils and monocytes, both in isolation and during formation of a static clot. Platelets generate over 100 molecular species on thrombin activation, and mice that lack the ability to generate these show a consumptive coagulopathy and are protected against atherosclerosis and aortic aneurysm. Our recent studies have characterised the biophysical mechanisms by which eoxPL promote blood clotting, and in this talk, our recent studies on their role(s) in vascular inflammation and hemostasis will be presented. We are currently extending our work to the characterisation of the role of these unique lipids in brain vascular health and disease, but this is very early stage so preliminary data on this will be presented.  

Host

Professor Paul Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@Imperial.ac.uk) to arrange to meet with the speaker

Venue

Location and timings tbc

 

5 March 2019

Robin Franklin

Guest lecture - 5 March
Professor Robin Franklin FMedSci
Professor of Stem Cell Medicine at the Wellcome Trust-MRC Cambridge Stem Cell Institute
The University of Cambridge

Host

Professor Paul Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@Imperial.ac.uk) to arrange to meet with the speaker

Venue

E519 Burlington Danes Building
Hammersmith Campus

Directions to the Hammersmith Campus and campus map are available on the College 'visit Hammersmith' web page

9 April 2019

Is it possible to prevent Alzheimer with multidomain interventions? 

Miia Kivipelto

Guest lecture - 9 April
Professor Miia Kivipelto
Department of Neurobiology, Care Sciences and Society
Karolinska Institutet 

Host
Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@imperial.ac.uk) to arrange to meet with the speaker

Venue
E519, Burlington Danes Building, Hammersmith Campus
Directions for finding Hammersmith Hospital are available on the College 'Visit Hammersmith' web page

Recent Seminars

Dr Lenore J Launer, Epidemiology to guide discovery

Using epidemiology to guide discovery: Repurposing drugs to prevent dementia - 19 June 2018

Lenore LaunerSpecial guest
Dr Lenore J. Launer
Senior Investigator, Chief, Neuroepidemiology Section
Intramural Research Program,
National Institute on Aging, NIH

Basing drug target identification on observational epidemiologic cohort studies has many unique advantages that complement other strategies for drug discovery. The case of hypertension as a risk factor for Alzheimer’s disease provides an example of using observational epidemiologic data to identify drugs that reduce AD risk. A brief overview will be given on blood pressure-brain epidemiologic and trial findings, as well as methodologic issues in studying these relationships. Preliminary data will be presented from a meta-analysis of population-based follow-up studies examining the risk for dementia-associated various anti-hypertensive medications.

Host
Dr Maksym Kopanitsa (m.kopanitsa@imperial.ac.uk)

Date and time
Tuesday 19 June 2018, 15:00 (with refreshments available from 14:30)

Venue
Praed Street seminar room, St Mary’s Faculty of Medicine Building
Directions for finding St Mary's Campus are available on the College 'Visit St Mary's' web page

Prof Seth Grant, Synaptome Mapping

Synaptome mapping: new technical approaches for unravelling the molecular architecture of synapses and the brain - 22 June 2018


Seth GrantSpecial guest
Professor Seth Grant, FRSE, FMedSci 
Centre for Clinical Brain Sciences
University of Edinburgh


Synapses are hallmarks of brain complexity – they are found in vast numbers and contain over 1,000 protein types. What is the purpose of this molecular complexity, how did it arise, and is there any logic to its organization?

We have addressed these issues using large-scale molecular approaches focused on the postsynaptic terminal of excitatory synapses. We found that postsynaptic proteins are hierarchically assembled into signalling complexes and supercomplexes, and these are distributed between synapses to generate synapse types. Whole-brain synapse maps revealed striking synaptic diversity and a “synaptome architecture” of the brain. Synaptome maps correlate with the structural and functional connectome, indicating that maps of synapse molecular diversity are features of systems-level organization.

We also analyzed the postsynaptic responses to elementary patterns of neural activity and a repertoire of innate and learned behaviours in mice with mutations in >50 postsynaptic proteins. The results of these experiments, together with the synaptome map data indicate that synapse diversity is a means of storing and recalling information in the brain. Synapse proteome complexity may generate a virtually limitless number of synapse types and synaptome maps offering immense information storage that can be accessed by patterns of activity. Autism and schizophrenia mutations disrupted the hierarchical assembly of supercomplexes and synaptome map architecture, the responses to sequences of activity and the behavioural repertoire.

Host
Dr Maksym Kopanitsa (m.kopanitsa@imperial.ac.uk)

Date and time
Friday 22 June 2018, 13:30 (with a light lunch available from 13:00)

Venue
E519, Burlington Danes Building, Hammersmith Hospital
Directions for finding Hammersmith Hospital are available on the College 'Visit Hammersmith' web page