genes - Erythos.com

Document technical information

Format ppt
Size 2.6 MB
First found May 22, 2018

Document content analysis

Category Also themed
Language
Type
not defined
Concepts
no text concepts found

Persons

Leonardo da Vinci
Leonardo da Vinci

wikipedia, lookup

David Nutt
David Nutt

wikipedia, lookup

Don Baldwin
Don Baldwin

wikipedia, lookup

John Axford
John Axford

wikipedia, lookup

Organizations

Places

Transcript

Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME):
pathogenesis, diagnostic biomarkers & clinical trials
Dr Jonathan R Kerr MD, PhD, FRCPath
Sir Joseph Hotung Senior Lecturer in Inflammation
St George’s University of London
Chronic Fatigue Syndrome (CFS)
Epidemiology
Prevalence of 0.5%
More common in females (6:1)
Sudden onset
Preceding virus infection (‘flu-like illness, outbreaks, specific viruses)
Exposure to toxins, chemicals, pesticides, vaccination
Pre-existing emotional stress
Chronic Fatigue Syndrome (CFS)
Studies of Pathogenesis
Immune system -
IC’s, IgG, B cells, NK
Th2 phenotype
cytokine dysregulation / chronic immune activation
Infection Nervous system -
virus, bacterium
Endocrine system Cardiovascular system Psychological function Genetic predisposition -
slight HPA axis
vasodilatation
depression & anxiety
deduced from twin studies
paresis, visual loss, ataxia, confusion
abnormal metabolism of 5-HIAA, A-V, 5-HT, PRL
brain scan abnormalities
Active infections / insults in 200 CFS patients
Enterovirus
Chlamydia pneumoniae
Epstein-Barr virus
Recurrent VZV infection
Parvovirus B19 infection
Hepatitis C virus
Cytomegalovirus
Postvaccination (pn, MMR or flu)
Toxic mould exposure
Recurrent HHV-6 infection
109
18
6
6
3
3
3
3
2
1
Unknown
44
Chia et al. Clin Infect Dis 2003;36:671-2.
Chronic Fatigue Syndrome (CFS)
Treatment
Graded exercise therapy (GET)
Cognitive behavioural therapy (CBT)
Immunological – IVIG, interferon, terfenadine,
Pharmacological – hydrocortisone, NADH, DA agonist, MAOI, Vit B analog,
galanthamine, fludrocortisone, antidep, SSRI, acyclovir, IFN inducer
Supplements – magnesium
Complementary / alternative – massage, osteopathy
Other – buddy/mentor program
specific treatment of virus infection
Hypothesis for prolonged fatigue / CFS
Insults
Initial processes
A
B
C
D
E
F
G
H
I
J
K
Final common pathway(s)
CFS
Overview of basic cell processes
Microarray
Microarray
GENES
Taqman real-time PCR
Test
gene
Control
gene
Pilot
study
Study of Gene Expression in
Chronic fatigue syndrome
Pilot study - 2005
Hypothesis: that abnormalities of gene regulation occur in CFS
25 CFS patients & 25 normal controls
Gene levels determined by Microarray analysis (9,522 genes) & real-time PCR
Pilot
study
16 CFS-associated Genes
Immune
IL-10RA
CD2BP2
IL-10 receptor alpha
CD2 antigen binding protein 2
Neurological
PRKCL1
GABARAPL1
KHSRP
NTE
GSN
Protein kinase C-like 1
GABA(A) receptor associated protein like-1
KH-type splicing regulatory protein
Neuropathy target esterase
Gelsolin
Mitochondrion
MRPL23
EIF2B4
EIF4G1
Mitochondrial ribosomal protein L23
Euk. translation initiation factor 2B, subunit 4δ, tv-1
Euk. Translation initiation factor 4G, subunit 1, tv-5
Apoptosis / cell cycle PDCD2
ANAPC11
BRMS1
PeroxisomeABCD4
PEX16
Transcription
POLR2G
Programmed cell death 2, tv-1
Anaphase promoting complex subunit 11 homolog
Breast cancer metastasis suppressor 1
ATP-binding cassette subfamily D, member 4
Peroxisomal biogenesis factor 16
RNA polymerase II (DNA-directed) polypeptide G
GENES
Pilot
study
Conclusion
A complex pathogenesis
Support for a biological process in CFS
Hypothesis
A working model of CFS
T lymphocyte
Macrophage
Hypothesis
A working model of CFS
T lymphocyte
Macrophage
cytokines, etc
GENES
What are the human and virus
gene signatures of CFS?
Phase 1-continued
Repeat microarray study
CFS patients and normal controls
Determine levels of ALL human and virus genes
Phase-1
cont.
Phase-1 continued Study
Clinical aspects
1. Diagnosis according to CDC criteria
(Fukuda et al, 1994)
2. Assessment of health & associated symptoms:
CIDI
Cantab
McGill
Chalder
MOS-SF36
SPHERE
Pittsburgh
GENES
Virus & Human genes in CFS
Microarray
study
Microarray
47,000 human genes
27 CFS pts / 54 normals
East Dorset CFS Service
MPSS
Study
MPSS
ALL genes sequenced
20 CFS pts / 20 normals
University of Cardiff
GENES
Microarray
182
MPSS
15
Immune Response
Neurological genes
Mitochondrial genes
Selective Regulation
52
Phase-1
cont.
GENES
GENES
GENES
Human microRNAs in CFS
GENES
Confirmation of specificity of CFS gene signature
Phase 2
Idiopathic CFS (n=500)
Infection-associated CFS (n=50)
Prolonged fatigue (n=50)
Normal fatigue (n=25)
Normals (n=100)
Rheumatoid arthritis (n=50)
Osteoarthritis (n=50)
Endogenous depression (n=50)
GENES
Associations of CFS-associated genes with symptoms
Phase 3
CFS-associated
symptoms
CFS-associated
genes
Time (12 months)
GENES
Virus genes in CFS
28 microbes
MPSS
Study
Known virus
triggers
28 microbes
Herpesviruses
Enteroviruses
Parvoviruses
Coxiella burnetii
Mycoplasma pneumoniae
Chlamydia pneumoniae
etc.
etc.
TREATMENT
DEVELOPMENT
Clinical trials of treatment candidates
Phase 4
Human
NFKB
IL-6
Interferon-b
HIF1a
T cell activation
Virus
Acyclovir
Pleconoril
Clarithromycin
Interferon-b
TREATMENT
DEVELOPMENT
Clinical trials of treatment candidates
Phase 4
Human
NFKB
IL-6
HIF1a
T cell activation
Virus
Interferon-b
Acyclovir
Pleconoril
Clarithromycin
Biomarkers
Development of a diagnostic test for CFS
SELDI-PC
Biomarkers
SELDI-PC
Biomarkers
Diagnostic test for CFS
**Collaboration with Dept of Paediatrics, Imperial College London
Clinical Centres
Acknowledgements
CLINICAL COLLABORATORS
Dr Selwyn Richards, Dorset CFS Service
Dr Janice Main, Imperial College London
Professor Terry Daymond, Sunderland
Professor Andrew Smith, University of Cardiff
Dr David Honeybourne, Birmingham
Dr Amolak Bansal, St Helier Hospital, Surrey
Professor Jon Ayres, Aberdeen University
Professor Robert Peveler, University of Southampton
Professor David Nutt, University of Bristol
Dr John Axford, St George’s University of London
Dr Russell Lane, Charing Cross Hospital, London
Dr John K Chia, UCLA Medical Centre, CA, USA
Dr Derek Enlander, NY, USA
Dr Paul Langford, Imperial College London
Professor Mike Levin, Imperial College London
FUNDING
CFS Research Foundation, Hertfordshire, UK
STUDY DESIGN & LABORATORY WORK
Deepika Devanur, St George’s University of London
Robert Petty, St George’s University of London
Beverley Burke, St George’s University of London
Narendra Kaushik, Imperial College London
Rob Wilkinson, Imperial College London
Clare McDermott, Dorset CFS Service
Jane Montgomery, Dorset CFS Service
David Fear, Kings College London
Tim Harrison, UCL
Paul Kellam, UCL
David AJ Tyrrell, CFS Research Foundation
Stephen T Holgate, University of Southampton
Emile Nuwaysir, Nimblegen Inc, USA.
Don Baldwin, University of Pennsylvania, USA
Peter Rogers, NBS
Diana Carr, NBS
Julie Williams, NBS
Frank Boulton, NBS
Andrew Bell, Poole Hospital

Similar documents

×

Report this document