WP6.2 Genomics and microbiology
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WP6.2 Genomics and microbiology. Overall Objective: To demonstrate how the integration of pathway biology And host/ pathogen genomics can contribute to clinical diagnosis and treatment of infected patients. 1 st Annual Technical Review, Brussels, 16 th March 2005. UEDIN. LEIC. INFORMA.

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Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Overall Objective:

To demonstrate how the integration of pathway biology

And host/ pathogen genomics can contribute to clinical

diagnosis and treatment of infected patients

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

UEDIN

LEIC

INFORMA

IMIM

FORTH

WP6.2 Genomics and microbiology

Work Package approach

To forge a collaboration between partners through

the integrated study of host/ pathogen interactions

WP6.2 Partners

Project Lead:

P Ghazal

K Robertson

M Mewissen

G Sing

A Livingston

T Brooks

M Alba

B Oliva

Joan Planas

Roberto Ricci

Maurizio Zazzi

M Reczko

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Host pathway: Interferon Signalling

> A family of related proteins

> Bind to specific receptors

Activation of Interferon signalling pathways results in a defined gene expression and:

Increased

antigen presentation

Inhibition of

cellular proliferation

Development of an

inflammatory response

An anti-infective state

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Interferon is a key Inflammatory mediator

with a number of notable therapeutic applications

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Medical Informatics

Bioinformatics

Viral Immuno-

modulatory

Interactions

Clinical

Host/ Viral

Interactions

Outcomes:

Secretome

1. Further insight into the virus-host interaction

2. Identification of biomarkers for validation

and potential therapeutic exploitation

3. Methods for storage, manipulationand

exchange of phenotype data

Protein Interaction Network

microRNA

Phenotype DB

Microarray/

Proteomic

Profiling

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Viral Immunomodulatory Interactions (IMIM/ UEDIN)

Objectives:

To characterise protein-protein interactions:

1. Within host interferon signalling pathway

2. Between virus and host proteins

Objective 1. Application of PIANA to identification of virus/ host protein interaction

PIANA

Yeast interactions experimentally

defined by yeast 2 hybrid approach

Gene

COG code

x

1

2

3

x

y

z

x

7 predicted CMV-Human

protein interactions

e.g. KPNA4

x

x

2. Interacting pairs in yeast defined

which have at least 1 COG code in

common with CMV proteins

1. COG codes assigned

to Human CMV proteins

3. Orthologous human

partner identified

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Viral Immunomodulatory Interactions (IMIM/ UEDIN)

KPNA4 (importin alpha 3)

Functions in import of IRF3

into nucleus from cytoplasm

Kumar KP, McBride KM, Weaver BK, Dingwall C,

Reich NC.Regulated nuclear-cytoplasmic

localization of interferon regulatory factor 3, a

subunit of double-stranded RNA-activated factor 1

Mol Cell Biol 2000 Jun 1;20(11):4159-68.

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Sub-cellular Logic Interaction map of interferon signalling pathway submodule

CMV dUTPase

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

How can a bioinformatics analysis of host-pathogen pathway interactions facilitate clinical patient management?

Anti-Retroviral Cohort Analysis (ARCA) db

> Stores clinical and HIV genome data (>3000 patients) from multicentric observational cohort in Italy

> Enables exploitation of HIV genotype data to advanced HAART therapy

230 patients identified

Multiple samples available

Full treatment history

HIV genotypic data available

Key Question: Can host bioinformatics pathway information be incorporated

into medical informatics DB and predictive models?

100 patients

Host

Pathogen

HLA typing

IFN genotyping

CMV status

Hepatitis G status

Curation into ARCA DB

Therapeutic modelling

Clinical Host/ Pathogen

Interaction data

IFN Knowledgebase

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Milestones and Objectives

Year 2

Year 3

Year 1

Project definition

(UEDIN, IMIM, LEIC, FORTH, INFORMA)

Data acquisition and curation

Protein to protein interactions defined

miRNA stem loop identification

Novel genes experimentally identified

Genotyping/ infection status

Data analysis &

Integration

Pathway Biomarker Validation

POC study on benefit from integrating clinical and bio- informatics

Biomarker definition

Project Plan

Preparation of

Publications

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Efforts towards characterisation of IFN signalling pathway and identification of potential/ novel genes/ proteins of (clinical) interest

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Objective 1:

Identification of a core set of interferon Gamma-related genes/ proteins around which initial studies of WP6.2 will focus

UEDIN

‘novel’

Genes

(300 – 400)

263 Core interferon gamma response genes identified

Human/Mouse,

Variety of cell types

Literature Review

Ingenuity

Pathway Assist

Core

Literature

‘novel’

genes

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Literature Review (PubMed)

Several Hundred gene/ gene products

Subjective/ Objective Reduction and assortment

Antigen Presentation

Jak/ STAT

IRF(s)

Apoptosis

Ingenuity

Pathway Assist

Further novel signalling interactions identified

Core genes for analysis

Annotation (inc hand-curated protein-protein interaction data)

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

Actual number of genes involved in interferon response likely to be >1000

A system is required for storage and application of data

‘Interferon Knowledgebase’

1st Annual Technical Review, Brussels, 16th March 2005


Wp6 2 genomics and microbiology

WP6.2 Genomics and microbiology

  • Year 1 aims for knowledgebase development:

  • 1) Web accessible repository of interferon signalling-related information

  • 2) Incorporate data generated in course of InfoBiomed project

  • Year 2 aims for knowledgebase environment

  • Incorporate further signalling pathway information (type 1 interferon, TLR

  • TNF-alpha) selected via objective criteria.

  • 2) To integrate database with GPX database and allow

  • rapid focussed analyses of microarray/ proteomic data

  • 3) Output signalling pathway information from database in XML

  • (SBML-like) allowing modelling/ simulation

1st Annual Technical Review, Brussels, 16th March 2005


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