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: zzg@shmu.edu.cn

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