Wednesday, 1 July 2009

Network based prediction of human tissue specific metabolism

Tomer Shlomi****

Metabolism is the essence of life. Metab0lic diseases are very common and cancer has abnormal metabolic phenotype. Metabolic networks are the best understood networks (??! what about moon-lighting and localisation and modification and allostery and ...).
Nodes are substrates edges are reactions.
Modelling Network Function
  • Kinetics - small scales need few nodes need ks
  • Topological analysis - graph theory - abstract
  • Boolean
  • Constraints based models - optimisation theory - steady state behaviour.
Constraint based modelling from Palsson (how is this related to MCA of Fell?)
Treat as series of black boxes with input (medium and nutrients) output is the biomass, we have chemical limits from thermodynamics and the matter constraints.

Multicellular means the different cell metabolisms pass inputs and outputs to each other through the medium between cells. Combine metabolic data with other data which is tissue specific - gene expression and single cell metabolic flux data. Concentrated on gene expression. RNA and protein levels are not well correlated because of translation rate and other factors. Protein level not well correlated to flux depends on degradation allostery etc.
Bilu 2006
Schuster et al
Fong et al

Look for consistency between flux and the gene expression data based on paths and outputs to check those paths are on that produce the outputs. Can have high expression but the control is at the metabolite level (Fell says this is the general case).

The Comparative Analysis Reveals Indepdendence of Developmental Process During Early Development in Frogs

Eugenia Maria del Pino ****

All flora and fauna on the Galapagos had to get there by drifting as they are 1000 km from the mainland. There are no frogs in the Galapagos - barriers to many species. There are 443 species of frogs in Ecuador. High species diversity 10-20% of all vertebrate species.

Can only study the development of frogs that breed in captivity. Model organism frog is Xenopus laevis - development better known than that of human beings. This is from South Africa. Three types of frogs studied in Ecuador including foam-nesting and marsupial. Foam-nesting frog develops rapidly eggs deposited in foam away from water. Different predations and environmental pressures that need rapid development.

Frogs beat a jelly into foam with the fertilised eggs inside. Two days after laying the tadpoles hatch. The embryos are white so they are camoflaged. Terrestrial nesting frogs and marsupial frogs develop more slowly. Dendrobatid frogs - terrestrial nesting include poison arrow frogs are territorial. Find a nest and then calls a female. Embryos cared for by father for 20 days tadpoles attach to the father who transports them back to the water. Pouch in marsupial frogs is on the back - male pushes the eggs into the pouch with his feet. Incubation is for four months then the female gives birth by opening the pouch. Physiology is similar to pregnancy. These are large eggs and can be 1cm in diameter whereas xenopus is 1.2 mm. Have an embryonic disk which is similar to chick development.

Development starts at the dorsal blastocore lip which grows to encircle the yolk plug and then the embryo will surround it. The egg has a polarity from the start - it knows where dorsal is. Needs to change from spherical to elongated. Brachyury is an important gene for development. Work carried our by Spemann-Mangold to identify organiser that if it is not properly located causes twining.

Pino paper

Goosecoid expressed in the dorsal blastocore lip. Identified as an organiser gene. Then Lim1 also identified so that there are manu different genes for the dorsal and even the ventral side of the egg.

Slow egg development means the slow elongation of the Archenteron. Lim1 and Brachyury are important genes. Developed antibodies for transcription factors Lim1 and Brachyury show they are nuclear. Slow development extension of the notochord only occurs after closure of the blastocore. So development is related to evolutionary properties. There is less pressure to form the elongated mobile tadpole and so elongation is delayed.

Computational comparative approaches are valid but there is a lack of molecular data in more exotic species.