A MULTI-TARGET APPROACH TO 'SYSTEMIC' DRUG----RAJESH S. GOKHALE

BIOLOGY BEYOND BORDERS

PARADIGM OF TB INFECTION: CAUSE INFECTION IN MANY BUT ACTIVE DISEASE IN FEW.

DYNAMIC INTERPLAY OF HOST AND PATHOGEN INTERACTIONS

SATGES OF TUBERCULOSIS INFECTION:

BUG TAKENS UP BY ALVEOLAR MACROPHAGES > PREVENTION OF PAHAGO-LYSOSOMES FROMATION AND RAPID BACTERIAL MULTIPLICATION > RELEASE OF CHEMOTACTIC SIGNALS

PROGRESSION OF GRANULOMA TO ACTIVE TUBERCULOSIS

Low-Cost Automation of Sputum Smear Analysis by Imaging Cytometry------Pavak shah

Smear Microscopy Advantages: Low Cost

Low-Cost imaging: low-magnification; LED excitation; CMOS camera sensor; fixed focus, fixed-stage; Smear analysis automation

Advantages: Low-cost; potential high sensitivity

Image Analysis: many possibilities, simplest approach: segment image by intensity threshold; more sophisticated strategy: shape space classifier

Why imaging cytometry?
low-cost, low-power; portable, easily ruggedized, temperature stable reagents, increses testing throughput.

Continued and future development: software- image analysis optimization

TB POC test------martin casenghi

TB diagnosis, closest POC test: Sputum smear microsope

TAG: Treatment Action Group

Medical needs priorities

The TB POC test Challenge: Ag and /or Ab detection, funding gap.

Alternative funding mechanism -TB diagnostic prize fund?

Glycomics---- Sulagana Banerjee

Glycosylation

carbohydrate interactions in a cell.

Why glycans?

Glycans: potential drug targets for drugs, vaccine candidates, enzymes processing glycans catalyze steps in growth, proliferation and infection diseases.

Through th Looking Glass--

Glycome in infection development: microbial adhesion > host penetration > host damage

Glycosysltion present in both prokaryotes and eukaryotes

Two types of glycans: N-Glycans and O-Glycans

Key components for targeting glycome: enzymes responsible for makin glycoconjugate; protein responsible for making cell surface.

Challenges for annotatinng the Mtb glycome: not much available literature.

Organisation of Glycome in Mtb:

Re-annotating Mtb using the power of collaboration

Search for homologues of glycans

Function prediction of unknown proteins

Pathway Modelling and Curationusing CellDesigner + Payao --Yukiko

CellDesigner

How to Build Pathway?

species (nodes)
reaction
litreature

Model Representation <> Modelling tools <> Databases

SBML (Systems Biology Markup Language)
SBGN (Systems Biology Graphical Notation):

MAPK pathway

SBML <> SBGN

Read SBML file, add graphical notation, stored in CD annotation

Database Connection

Annotation:
Notes: model, species, protein/RNA/DNA;
MIRIAM;
Layer text

Simulation: via control panel; via SBW menu

SBW= systems biology workbench

SBML features and supporting tools

Models For Simulation

Plugin Development

Model Curation

Pathway Modelling Case Study

Mapathon: 15 members: ERATO wet lab virologists/biologists etc.
read 60 papers

Payao: community base pathway enrichment paltform

Public> Map> Community A

COMPUTATIONAL SYSTEMS BIOLOGY- Tools & aPPLICATION-Samik Ghosh (The System Biology Institute)

PART I

PATHWAY CURATION TOOLS AND APPLICATION

Complexity: Guess which body was not designed to stand turbulence?

Post genomic era has opened up huge database cataloguing the molecular parts of biological systems; Comprehansive knowledge of isolated systems available 'in vitro' and in vivo; Comprehanding paradigm shift

Computational Approach:

Model-Modify-Mine-Measure

Biological Modelling and simulation:

Body waeight> Tissue/cells > Protein > Genes (Top-Down: increasing complexity but Bottom-Up: increasing abstraction)

System biology Approach: network model construction (clinical data, animal models, biologicalliterature); network property analysis (pathway length distribution, node centrality distribution, network degree distribution); high granularity pathway dynamic modelling (celldesigner.org)

Computational Platform:

GN (graphical notation), SBML, CellDesigner.org, CellDesigner Applet, Public Donation Database




PART II

Mtb Mappathon

System Biology

whole > sum of its part

What system biology not... NOT a black office, NOT a Spherical Cow',

A matter of sacle- physics, chemistry , biology

A Fundamental Difference-- physics, chemistry= predictive, but, biology= observational

Making biology a predictive science

why do we need computational modelling?

A new way of drug design- system focus<- target focus<- legend focus Reconstruction of Metabolic Networks Practice of systems biology Stoichiometric Analysis- capture the structure of metabolic network, does not require quntitative kinetic parameters, FBA (Flux balance analysis) Work Flow of FBA -- Development of pathway model-> computation of stoichiometric matrix-> FBA-->in silico gene deletions-> drug perturbations-> identification of protein essential to pathway-> Drug target

Mycolic Acid Biosynthesis Pathway

Reactome Modelling -- Pathway Modelling (FBA), Network Modelling

Reaction Networks: Comparative Analysis

targetTB: Target Identification Pipeline

Network Analysis- Node deletions: change in netwok parameters; Lethal Deletions

Interactome Construction

Structure Analysis

PocketDepth: Binding pocket detection

PocketMatch- A new algorithm for Binding site comparison

Protein-Protein Influence Matrix: identify maximally connected code; Preliminary analysis shows hub involvement.

High Order Interactions: Pathway-Pathway; Process-Process

Pathways to Drug Resistant

Model Summary: model construction from litreature, Boolean construction, 75 nodes are present.

State MAP for simulations

MAP of single & double knock-outs

work flow- host pathogen modelling: advantage of modelling- bird's eye view for host-pathogen interplay

Genomics-> Proteomics-> System Biology