Translating Humour - The Problems Of Translating Terry Pratchett
The Funder’s Perspective: Multi-morbidity and Translating ...
Transcript of The Funder’s Perspective: Multi-morbidity and Translating ...
Speaker: Professor Paul Elliott
Chair of MRC Population and Systems Medicine Board
Professor of Epidemiology and Public Health Medicine
Imperial College London
Cardiovascular, Metabolic and Kidney Disease: Crosscutting Science and Best Practice in Multi-morbidity
Royal College of Physicians, London, 1 July 2019
The Funder’s Perspective: Multi-morbidity
and Translating Basic Science into the
Best Clinical Trials
MRC | Medical Research Council
MRC delivery plan 2019: priorities
MRC | Medical Research Council
Working definition (AMS April 2018 report)
Co-existence of two or more chronic
conditions, each one of which is either:
• A physical non-communicable disease
of long duration, such as a
cardiovascular disease or cancer.
• A mental health condition of long
duration, such as a mood disorder or
dementia.
• An infectious disease of long duration,
such as HIV or hepatitis C.
Multimorbidity – challenge for health care systems
• Co-existence of two or more chronic conditions
• 1 in 4 adults affected
• Treatments of long-term conditions ~70% of NHS expenditure
Violan et al. PLoS ONE 2014; 9:e102149 Garin et al. J Gerontol A Biol Sci Med Sci 2016; 71:205-14
MRC | Medical Research Council
Multimorbidity workshop June 2018: UK priorities
• Capitalise on existing investments (e.g. UK
Biobank, Health Data Research UK)
• Understand implications of polypharmacy (e.g.
drug–drug interactions, adverse reactions)
• Develop/ evaluate strategies for prevention/
treatment of multimorbidity, initially focusing on
the most common clusters of conditions
• Explore possible common mechanistic
factors underlying concurrent conditions
(e.g. inflammation)
MRC | Medical Research Council
Multimorbidity workshop June 2018: priorities for LMICs
• Data resource auditing: e.g. (longitudinal) population
studies, health and demographic surveillance surveys
• Local, context-specific burdens and risk factors
• Life-course perspective to help prioritise limited resources
and target healthcare to those most in need
• Primary prevention: a systematic assessment of the
impact of upstream, population-based primary prevention
strategies
• Intervention development: evaluation of simple, scalable,
and technologically enabled interventions, including new
models of care and community-centred approaches, initially
targeting common disease clusters.
• Health economic analyses and policymaker engagement
To a systems biologist pathology is just a change in phenotype!
Most human diseases are connected at some genetic level
Cardio-vascular
CancerMetabolic
Disease gene network
Barabasi et al (2007)
MRC | Medical Research Council
To a systems biologist pathology is just a change in phenotype!
Most human diseases are connected at some genetic level
Cardio-vascular
CancerMetabolic
Disease gene network
Barabasi et al (2007)
“Genetics loads the gun, but
Environment pulls the trigger”After Elliott Proctor Joslin MD, Br Med J 1991; 302: 1231
Tzoulaki et al. Circulation 2016; 133:2314-33
Surgeon General’s Report 2014
Diseases causally
linked to smoking
added in 2014 Report
Mutational signatures associated with smoking
Alexandrov et al. Science 2016;354:618-22
1: ketoleucine, 2: leucine, 3: valine, 4: 2-hydroxyisobutyrate, 5: alanine, 6: lysine, 7: N-acetyl signals from urinary glycoproteins, 8: N-acetyl neuraminate, 9: phenylacetylglutamine, 10: glutamine, 11: proline betaine, 12: 4-cresyl sulfate,13: succinate, 14: citrate, 15: dimethylamine, 16: TMA, 17: dimethylglycine, 18: creatinine, 19: ethanolamine, 20: O-acetyl carnitine, 21: glucose, 22: 3-methylhistidine, 23: glycine, 24: hippurate, 25: pseudouridine, 26: NMNA, 27: 3-hydroxymandelate, 28: tyrosine, 29: 4-hydroxymandelate, 30: formate, U1 to U26 unidentified
Inflammation
• IL6R variants affect inflammatory
markers and risk of CHD
• Monoclonal antibody tocilizumab
blocks IL6R, used in treatment of RA
• IL6R signalling target for
prevention/treatment of CHD?
IL6R MR consortium Lancet 2012;379:1214-24
Diabetic kidney disease is the most common cause of ESRD in UK
Source: UK Renal Registry
“Type 3 diabetes” - Alzheimer’s linked diabetes
Diabetes and Albuminuria not good for cognition
INSULIN RESISTANCE AS A DRIVER OF ALZHEIMER’S
TERMINALLY DIFFERENTIATED
The Expression and Significance of Neuronal IconicProteins in Podocytes
Yu Sun1, Hongxia Zhang2, Ruimin Hu1, Jianyong Sun3, Xing Mao1, Zhonghua Zhao1, Qi Chen1,
Zhigang Zhang1*
1 Department of Pathology, Key Laboratory of Molecular Medicine, Chinese Ministry of Education, Shanghai Medical College, School of Basic Medical Science, Fudan
University, Shanghai, P.R. China, 2 Department of Pathology, Weifang Medical University, Weifang, Shandong, P.R. China, 3 Institute of Health Sciences, Shanghai Institutes
for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
Abst ract
Growing evidence suggests that there are many common cell biological features shared by neurons and podocytes;however, the mechanism of podocyte foot process formation remains unclear. Comparing the mechanisms of processformation between two cell types should provide useful guidance from the progress of neuron research. Studies haveshown that some mature proteins of podocytes, such as podocin, nephrin, and synaptopodin, were also expressed inneurons. In this study, using cell biological experiments and immunohistochemical techniques, we showed that someneuronal iconic molecules, such as Neuron-specific enolase, nestin and Neuron-specific nuclear protein, were also expressedin podocytes. We further inhibited the expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxyterminal hydrolase-1 by Small interfering RNA in cultured mouse podocytes and observed the significant morphologicalchanges in treated podocytes. When podocytes were treated with Adriamycin, the protein expression of Neuron-specificenolase, nestin, synaptopodin and Ubiquit in carboxy terminal hydrolase-1 decreased over time. Meanwhile, themorphological changes in the podocytes were consistent with results of the Small interfering RNA treatment of theseproteins. The data demonstrated that neuronal iconic proteins play important roles in maintaining and regulating theformation and function of podocyte processes.
Citat ion: Sun Y, Zhang H, Hu R, Sun J, Mao X, et al. (2014) The Expression and Significance of Neuronal Iconic Proteins in Podocytes. PLoS ONE 9(4): e93999.doi:10.1371/journal.pone.0093999
Editor: Giovanna R. Mallucci, University of Leicester, United Kingdom.
Received October 17, 2013; Accepted March 10, 2014; Published April 3, 2014
Copyright : ß 2014 Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by a grant from the National Nature Science Foundation of China (NFSC: 81070566). The funders had no role in study design,data collection and analysis, decision to publish, or preparat ion of the manuscript.
Compet ing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
Int roduct ion
Podocytes are one of the types of glomerular resident cells,
which are characterized by their arborized cellular architecture,
with thick major processes and thin foot processes. The thin foot
processes and GBM cooperatively construct the glomerular
filtration barrier, which can effectively prevent proteins from
passing through. The fine cellular architecture of podocytes is
often altered; when podocytes are injured in certain pathophys-
iological conditions or in nephropathies, which are called
podocytopathies, such as process effacement, false microvillus
structures that formed from excessive cytoplasmic spinesextending
and the fracture or lose of the foot processes. These alterations
may increase the permeability of the glomerular filtration barrier
and cause massive proteinuria. Therefore, the maintenance of the
special morphology construction of the podocyte is thought to be
essential for its normal function. This morphology not only forms
the unique shape and filtration function but also plays important
roles in material metabolism, cell movement, energy and
intracellular information transmission [1]. The elucidation of the
mechanism of podocyte foot process formation is important for
determining approaches to the prevention and control of
nephropathy.
The mechanism of podocyte foot process formation remains
unclear. However, several current studies have shown that there
are many common cell biological features shared by neurons and
podocytes. Naoto Kobayashi et al. revealed that podocytes had an
extraordinary similarity with neurons [2]. Both cells are highly
differentiated with similar long and short cell processes that are
equipped with highly organized cytoskeletal systems. Additionally,
the two types of cells share the expression of structural and
regulatory proteins, such as synaptopodin, drebin and desin [3].
Synaptopodin, which is the major component of the podocyte
cytoskeleton, is primarily expressed in the site of the terminal
processes of podocytes. Moreover, this protein can also be
expressed in neuronal dendritic spines [4]. In addition, more
recent data have shown that podocyte processes also share the
expression of some special proteins, such as nephrin and podocin,
with neuronal dendrites [5–8].
Moreover, some molecules that are abnormally expressed may
be involved in the pathological states of brain and kidney tissues.
For example, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1),
which is a member of the deubiquitination enzyme family, is
specifically expressed in the brain, testis and kidney tissue under
normal circumstances [9–12]. The abnormal expression of UCH-
L1 in neurons is usually related to some degenerative diseases,
such asParkinson’sdisease, in which dopamine and other proteins
PLOS ONE | www.plosone.org 1 April 2014 | Volume 9 | Issue 4 | e93999
PODOCYTES NEURONES
TERMINALLY DIFFERENTIATED
? COMMON CELLULAR MECHANISMSThanks to Richard Coward
MRC | Medical Research Council
Long-term ambitions in addressing multimorbidity
• Identify patterns and trends in disease clusters,
building on well-powered, extensively phenotyped
epidemiological data
• Move away from a one-disease, one mechanism
approach and understand the common root causes of
multimorbidities
• Take a whole-systems approach to better understand
the dynamic relationship within and between biological
and social factors linked to multimorbidity
• Build on well-powered, highly phenotyped longitudinal
population and patient cohorts to discover entirely new
indicators of co-morbid diseases and disease
modification in pre-symptomatic individuals.
MRC | Medical Research Council
Coordinated support of research on multimorbidity
Identifying
research enablers
& barriers
Pump–priming
activity
Priority setting
Research at scale
Better therapeutic Targets
Polypharmacy
‘Real world’ clinical trials
Prevention
• PSMB Research Opportunity Area