Role of genomics, proteomics and metabolomics in regulation Applied genomics, Nutritional genomics

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Role of genomics, proteomics and metabolomics in
regulationApplied genomics,Nutritional
genomics
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Converging effects
Information technology
Genetics
On-line consultations Diagnostic
databases Simulation by models Image
analysis Drug discovery... Functional foods
Patient/consumer tailored Medicine, pharmacology,
Nutritional sciences, etc
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Bioinformatics Renaissance

• Large amounts of data
• (genomic, biochemical, functional, phenotypic,
  etc)
• Algorithms for pattern recognition and
  comparisons of biosystems
• on different levels of organization (genomic,
  gene networks, structures)
• Need for data integration and distributed
  technologies
• Scalable computational resources
• Emergence of Systems Biology Approach

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Our view on Biology as Systems Science
Integrated Whole vs. Parts

• Cartesian view any complex system can be
  analyzed in terms of properties of its parts
• Systems approach Living systems are integrated
  wholes whose properties cannot be reduced to
  those of the parts
• Systemic properties arise from a
  configuration of ordered relationships
  characteristic of a particular class of organisms
  or systems.
• Systemic properties are destroyed when a system
  is dissected into isolated elements
• (N.Maltschev, Argon Antl. Lab.)

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Biological networks
Intracellular regulations Cell-cell
communications Organ networks/homeostasis
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Biological information
DNA (gene sequences)
3D structure of proteins
Biological papers
Protein sequences
Genetic papers
Human genetic maps
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The automated production line for sample
preparation at the WhiteheadInstitute, Center
for Genome Research. The system consists of
custom-designed factorystyle conveyor belt robots
that perform all functions from purifying DNA
from bacterial cultures through setting up and
purifying sequencing reactions.
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Main health-related challenges

• Cardiovascular
• Cancer
• Diabetes-obesity
• Undernutrition/malnutrition
• Infectious diseases
• Allergies
• Ageing process

Complex biological problems! Polygenic
environmental effects!
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Human Genome Project

• Approx. 5 billion nucleotides
• 1,5-3 million of SNP (single nucleotide
  polymorphism
• Approx.
• 20 thousand human gene
• Genome- Brown TA ed.,
• Bios Scientific Publishers 2002

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High blood-pressure heart disease
Obliteration of Coronary vessels
AGE
Phenotype is under the control of Genetic
and environmental effects
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Genomic research looking for 20.000 needles in
23 haystacks
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GENOMIC PRIORITIES IN THE BUDGET OF THE EU
Million Euros
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Bioactive food (or drug) components can modify
transcription, translation and metabolism
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Effects of selenium on certain genes
Cancer Res, 2002
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Bioactive food/drug componentsgenetic,
epigenetic and proteomic effects
Milner J Nutr 2004
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Partial list of bioactive food componentswith
possible effects on cancer
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Inter-relationship between bioactive food/drug
components and events involved in the cancer
process
Exampl Indoles, flavonoids
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Example-Nutrients Fate and activities of
nutrients in the cell

• may act directly as
• ligands for transcription factor receptors
• (pathway A)

Kaput J, Physiol Genomics 2004
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Fate and activities of nutrients in the cell

• may be metabolized by
• metabolic pathways
• ?
• altering concentrations of substrates /
  intermediates (pathway B)

Kaput J, Physiol Genomics 2004
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Fate and activities of nutrients in the cell

• May be involved in gene regulation
• or cell-signaling (pathway C)

Kaput J, Physiol Genomics 2004
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Nuclear receptors, dietary ligands
Kaput J, Physiol Genomics 2004
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Micronutrient deficiency - DNA damage with
health effects
From Kaput J Physiol Genomics 2004 Ref 2
Ames, Toxicol Lett 1998
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Example for applied genomics Nutrigenomics and
nutrigenetics two sides of a coin

• For personalized nutrition
• effects of diet on body-metabolism
• influence of genotype on nutritionally related
  diseases
• must be considered

Mutch, FASEB 2005
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Metabolic functions of nutrients and drugs-- a
reductionist approach

• To minimize the analytical limitations of each
  technique
• It combines at least two of the three principle
  platforms
• and focuses on common changes by
  platform-specific statistical models
• ?
• Unraveling the roles of nutrients in the
  biological system.

Mutch, FASEB 2005
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Elliot, BMJ 2002
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Nutritional consequences of cellular process
with genetic polymorphisms
Haemochromatosis http//www.ncbi.nlm.nih.gov/book
s/bv.fcgi?ridgnd.section.251reftoc
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Nutritional genomics and biomarker discoveryThe
steps involved in gene expression
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Nutritional genomics and biomarker
discoveryDiet (nutrients) can modulate these
processesfrom cellular level to populational
level
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Nutritional genomics and biomarker
discoveryFunctional genomic techniques can
analyzeeach stage, with appropriate biomarkers
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Assesment of nutrient requirements by omics-
based analyses
Joung J.Nutr 2001, Oliver Nature 2000, Go J.
Nutr 2003
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Example DETERMINATION OF SPECIFIC METHYLATIONBY
CHEMICAL MODIFICATION

• Methylation of cytosines in CpG dinucleotides is
  an inherited epigenetic modification that is
  responsible for both functional activity of
  certain genomic loci and total chromosomal
  stability.
• Studies of methylation are aimed at
• searching for new methylation hot spots, and also
  
• mapping of unmethylated CpG sites
• Bisulfite sequencing is based on the reaction of
  bisulfite anion (HSO3-) with cytosine resulting
  in production of a sulfonated derivative, which
  is rapidly deaminated.
• During the subsequent replication, uracil,
  generated instead of cytosine, will produce
  hydrogen bonds with adenine,
• and this will cause transition in this site in
  one of the daughter chains.
• 5-Methylcytosine is sulfonated incomparably more
  slowly.

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Stover Physiol Genomics 2004
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Genetic polymorphisms, nutritional and immune
status
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LC-PUFA Long chain polyunsaturated fatty acids

• A typical example of complex, bioactive
  molecules in nutrigenomics

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• Epidemiological studies on LC-PUFA
• Consumption of LC-PUFA beneficially affect
  physiological processes such as
• growth, neurological development,
• lean and fat mass accretion,
• reproduction,
• Innate and acquired immunity,
• infectious pathologies of viruses,
• bacteria and parasites
• the incidence and severity of virtually all
  chronic
• and degenerative diseases
• cancer, atherosclerosis, stroke, arthritis,
• diabetes, osteoporosis, and neurodegenerative,
  inflammatory and skin diseases

LC-PUFA Long chain polyunsaturated fatty acids
Mutch, FASEB J 2005
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According to microarray studies LC-PUFA can
mediate the functions of several transcription
factors, cell-cycle regulatory genes, RNA
transcription processes, prostaglandin
synthesis, inducible nitric oxide synthase
and related proinflammatory genes
Modern nutrigenomic technologies bioinformatics
can to reveal the complexity of LC-PUFA signaling
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Biological network triggered after the
consumptionof LC-PUFA

• LC-PUFA actions are mediated by
• transcription factors, such as PPAR and SREBP.
• Highlighted in blue
• are known functional and /or physical
  interactions between
• PPAR- and other genes

Mutch, FASEB 2005
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Further worksmall inhibiting RNA technology,
alternate analytical platforms (proteins,
metabolites) etc. can clarify the biological
functions,mediated by dietary lipids.
Modern nutrigenomic technologies bioinformatics
can to reveal the complexity of LC-PUFA
signaling
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Microarray-technics, examples New possibilities

• Network-conception
• (new way of gen-hunting ) Clue-genes in the
  comples chain of genes
• Connectivity map- Lamb J, Science 2006 sept

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Biological networks
Aim To identify key genes, with central
role. Identification with computational
modelling (Idea more links, more significant
role ! To prove by association studies
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Interrelated strategies for researchon
nutraceuticals and functional foods