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Agenda• Introduction to Ingenuity• Sample Studies:
– IPA in Biomarker Discovery Research– IPA in Copy Number/Disease Mechanism Research– IPA in Metabolic Disorders– IPA in Metabolomics & Molecular Toxicology
Discover the Biology 3
• Ingenuity Systems is the leading provider of products and services that enable analysis and exploration of biological data– There is more data to analyze and explore
then there is time or resources– Need to understand biological systems at
molecular, cellular and organismal level– Essential to have the right content and tools
for the job
• User base reflects strong adoption in research community– Top pharmaceutical companies – Large biotechs – Academic and government research labs
Partial Customer ListIngenuity Systems
Discover the Biology 4
ExperimentalPlatforms
Expression Arrays Proteomics Traditional Assays
ApoptosisApoptosis AngiogenesisAngiogenesis
CancerCancer
MoleculesFasFas VegfVegf
CellularProcesses
DiseaseProcesses
Systematic Generation of NovelBiological and Therapeutic Insights
The ChallengeData Analysis Across Multiple Dimensions of Biology
Informed in vivo, in vitro assays
Generate hypothesis of molecular mechanism
Find genes implicated in
disease
Identify related cellular processes, pathways
Discover the Biology 5
ExperimentalPlatforms
Expression Arrays Proteomics Traditional Assays
ApoptosisApoptosis AngiogenesisAngiogenesis
CancerCancer
MoleculesFasFas VegfVegf
CellularProcesses
DiseaseProcesses
Systematic Generation of NovelBiological and Therapeutic Insights
The ChallengeData Analysis Across Multiple Dimensions of Biology
Drug Treatment
Toxicological Responses
Xenobiotic Insult
Drug InducedInjury/Pathology
Discover the Biology 6
Solution Value
IPA is a software application that enables researchers to analyse & understand the complex biological and chemical systems at the core
of life science research
The Solution:Ingenuity Pathways Analysis
Discover the Biology 7
Discovery
Understand disease processes, identify
and validate targets
Providing Value Throughout Drug Discovery & Development Process
BiomarkersIdentify novel biomarkers,
understand their role in disease
pathways
Pharmacogenomics
Gain insight into differential response to therapeutics
Toxicology
Identify potential mechanism of
toxicity
Full bibliography available at www.ingenuity.com
Ingenuity Publications
528
The Ingenuity Platform
9
Ingenuity Pathways Knowledge Base
• Ingenuity Ontology of ca. 600,000 biological objects and processes in 12 major branches
• Robust, up-to-date synonym library• Knowledge Infrastructure tools and
processes for structuring biological and chemical knowledge
• ~ 1.8 million findings manually extracted from full text
• ~160 curated metabolic and cell signaling pathways
• Chemical and drug info• Signatures• Scalable best-in-class Content
Acquisition processes
Ontology and Knowledge Infrastructure Client Solutions
Portal & Enterprise Search Enablement
Ingenuity Pathways Analysis
Specialist Analytics
Enterprise KM Infrastructure
Ingenuity Pathways Knowledge BaseDatabase that is the core of Ingenuity’s Solutions
• The IPKB is a database that houses the most context-rich, high quality content available
• Expert Extraction from full text of journals• Current coverage of ~300 journals, plus review
articles and textbooks• Manually extracted by trained Ph.D. scientists
• Biological Database Import: • OMIM, GO, EntrezGene
• Internally curated knowledge:• Signaling & Metabolic Pathways• Drug/Target/Disease relationships
• All findings structured for computation• Ingenuity Ontology covers protein, gene, protein
complex, cell, cellular component, tissue, organ, small molecule & disease concepts and their interrelationships
Discover the Biology 14
Simple Data Upload Process• Flexible upload
process eliminates time consuming file formatting steps
• Supports analysis of id lists with mixed identifiers
• Stream lined workflows through 3rd Party vendors
• API capabilities
•Array identifiers•Gene identifiers•Protein identifiers•Metabolomic identifiers
Agenda• Introduction to Ingenuity• Sample Studies:
– IPA in Biomarker Discovery Research– IPA in Copy Number/Disease Mechanism Research– IPA in Metabolic Disorders Research– IPA in Metabolomics & Mol. Toxicology Research
IPA in Biomarker Discovery Research
• Goal of study: Identify diagnostic biomarkers for RA from rat transcriptomic and human proteomic data
• Results: multiple inflammatory pathways are perturbed across all data sets (Toll Like receptor signaling and IL6 & IL10 signaling). Multiple genes associated with chemotaxis of leukocytes upregulated in both mRNA and protein levels. Putative biomarkers supported by previous experimental data findings e.g CCL5
• Specific bottleneck addressed by IPA: Anchoring of molecular profiles to phenotypes associated with RA. Integration of data from multiple platforms (transcriptomic and proteomic) and disease models (CIA in rat & Erosive RA in humans). Confirmation that putative biomarkers identified are available in suitable biofluids.
Genomics dataSpecies: rat
Proteomics dataSpecies: human
Several pathways are commonlyperturbed across multiple datasets – including IL-6 signaling, IL-10 signaling and Toll-like receptor signaling.
Do known phenotypes e.g leukocyte counts in Erosive RA patients correlate with cellular processes?
Many genes that regulate “chemotaxis of leukocytes” were elevated, giving confidence that profiles generated from both approaches can be anchored to biological processes central to rheumatoid arthritis.
CCL5 expression has already been implicated in rodent models of collagen induced arthritis.
In particular, Gene View’s for CCL4, CCL5, S100A8 and S100A9 confirmed that assays are available for detection of human proteins from peripheral blood samples.
IPA in Copy Number/Disease Mechanism Research
• Goal of study: Identify genes relevant to malignancy in melanoma samples using SNP copy number analysis
• Results: IPA analysis of Chr.3 amplified region showed multiple genes associated with cancer and controlled by known cancer regulating genes. Multiple molecular relationships identified between genes amplified in Chr.3 region and genes previously associated with melanoma.
• Specific bottleneck addressed by IPA: Association found between Chr3 genes amplified in copy number and cancer. Specifically between MITF and melanoma.
Genes amplified in Chr. 3 (outlined in red) directly are implicated in cancer-related processes.
They also directly regulate or are regulate by other genes known to impact cancer pathways (outlined in blue).
For example:
IPA Analysis Highlights Networks of Amplified Genes Related to Cancer
Genes shaded gray are from the initial amplification region in Chr. 3 of melanoma cell lines.
Genes with a white background are implicated in melanoma development, based on evidence from the Ingenuity Knowledge Base.
Use the Connect feature to see if the Chr.3 genes are particularly enriched for connections to melanoma genes.
My Pathways Identifies Regulatory Events Connecting Sets of Genes
Chr.3 amplified genes IPA Melanoma Genes
Connecting amplified region genes to melanoma implicated genes shows a connectivity dominated by MITF
Many of the melanoma genes lie outside of the original amplified region of Chromosome 3 identified by Affymetrix analysis.
Understanding whether those genes undergo copy number changes in the melanoma cell lines will lend further evidence that these melanoma pathways are perturbed.
My Pathways Reveals Strong Connections Between Genes in Amplified Region of Chr. 3 and Melanoma-Related Genes
IPA in Metabolic Disorders Research
•Goal of study: Analyse and compare gene expression profiles in skeletal muscle tissue from 8 patients with morbid obesity (MO) to identify molecular mechanisms associated to abnormalities in energy expenditure.
•Results: Perturbed energy pathways such as Cardiac ß -adrenergic signaling and biological functions associated to dysregulated genes. Genes associated with synthesis of protein identified in skeletal muscle tissue from morbid obesity patients
•Specific bottleneck addressed by IPA: The IPA CoreTM and Comparison analysis identified pathways and biological functions associated to dysregulated genes in skeletal muscle tissue from a subset of morbidly obese patients. Patients subgrouped based on relevant biological functions and canonical pathways
Canonical Pathways across patients
Multiple Canonical Pathways cluster across patients 4-7
Cardiac ß -adrenergic Signaling:MO4
Impaired Cardiac ß -adrenergic signaling in skeletal muscle tissue is associated with defects in diet-induced thermogenesis that play a role in the development of morbid obesity.
Comparison Functional Analysis groups patients and shows role for protein biosysnthesis in obesity
Protein synthesis scores significantly in a subset of MO patients (MO4-MO7). Protein synthesis capabilities are thus impaired in subset of MO patients that includes individuals MO4-MO7.
Declines in the rate of biosynthesis of proteins in skeletal muscle tissue are correlated with the onset of insulin resistance and obesity.
Also, biosynthesis of protein is an important "futile cycle" that may function in adaptive thermogenesis and protection from diet-induced obesity through the consumption of ATP.
E
Protein Synthesis featured heavily for a single network
in patients 4-7
MYCN forms a common link between most of the down-regulated genes related to
the synthesis of protein
It seems likely that MYCN activity is down-regulated in skeletal muscle tissue of
patient MO4, and that reduced activity of MYCN protein is responsible for the lowered expression
levels of many of the genes related to synthesis of
protein
Networks show clustering of dysregulated genes around a single controlling node
• Goal of study: Monitor global changes in metabolite levels in the liver and serum of AAP treated mice to obtain insights into the disruption of metabolic pathways related to hepatotoxicity and to identify potential biomarkers of acute liver injury. Compare and contrast with a similar study investigating the gene expression changes associated with AAP treated mice.
• Results: Glutathione and Taurine Metabolic pathways implicated in cellular response to AAP exposure at both metabolite and mRNA level. Established toxicological pathologies associated with perturbed metabolites and genes.
• Specific bottleneck addressed by IPA: overlaying and analysis of metabolites and genes together onto established metabolic pathways.
IPA in Metabolomics & Molecular Toxicology Research
Proprietary and Confidential 28
Significant down-regulation of glutathione (GSH) as well as glutathione disulfide (GSSG) and glycine.
Overlay Expression Values from gene expression study of APAP treated mice (same dose.
Proprietary and Confidential 29
Glutathione Metabolism in Context of Metabolite and Transcriptome Data
Increases and decreases in metabolite
levels fits well with normal
role of metabolites in liver damage.
Proprietary and Confidential 30
Functional Analysis Maps Metabolite Changes to Known APAP Induced Hepatotoxic Phenotypes
Understand metabolite level changes in the
context of their effect on cellular, organismal
phenotypes.
Decreased levels of glutathione suggest
a net effect of increased liver
damage.
Proprietary and Confidential 31
Effects on Function Analysis Highlights Potential Impact of Metabolite Changes
Networks integrate metabolic reactions with signaling and
regulatory relationships.
Dynamic nature of networks highlights relevance to Taurine
metabolism.
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Networks Highlight Interplay Between Metabolites, Genes, Pathways
Computational Pathways Analysis Accelerates Biological Understanding
• Ingenuity Pathways Analysis allows scientists to – Simultaneously analyse and compare multiple
datasets from different patient populations, different platforms, etc.
– Gain a deeper biological understanding of the molecular and cellular mechanisms that distinguish one biological condition from another
– Graphically visualise biological interactions, processes, and pathways as they change over time, dose or disease progression
– Substantially decrease analysis time of microarray and other high-throughput datasets
Ingenuity Systems• Free, 2 week, fully functional trial:• www.ingenuity.com
• Contact details:• Adam Corner
• Brian Dron– [email protected]
