MedicineGiga research researchers from the University of Liege discovered that microRNAs are involved in asthmahttp://www.bulletins-electroniques.com/actualites/67768.htmThe latest research shows how asthma is a complex disease. Comparing
with an asthmatic lung that of a healthy person, it is possible to
identify many genes involved in this chronic respiratory disease. Giga
research researchers from the University of Liège interest, for them,
very small genetic sequences, called microRNAs, composed of twenty
letters (ACTG) away. They come from this region very mysterious genome, called non-coding, which was believed until recently that it was useless. Obviously wrong ...
It often takes him the evening before going to sleep, or outright overnight. Lucas wakes up coughing, calls his mom ... It can no longer breathe normally. It expires loudly, as if a veil had been placed on his lungs. He had an attack of asthma. it also sometimes foggy weather when it will play a football match. Or when he participated in the campaign in the old family home filled with dust. In general, a puff and blow it restarts. But crises can last several hours. Like her mother, like her brother, Lucas is allergic. He passed the tests in the pulmonology department of the CHU of Liège. Conventional diagnosis: asthma associated with allergy to cat hair in the house dust, etc..
They are approximately 750,000 people in Belgium asthma as Lucas, about 8% of the population. This rate can reach 15% in some countries, like the United States or Ireland. Fortunately,
current treatments (cortisone), most can live more or less normal and
may even expect a virtually complete disappearance of symptoms once
reached adulthood. But in a minority of patients, asthma can also occur in extremely severe. "This
is a potentially fatal disease, says Didier Cataldo, pulmonologist at
the University Hospital of Liège, Lecturer (Department of Biomedical
Sciences and preclinical) at the University of Liège. Estimated that the
disease kills 250,000 people each year worldwide. In
addition, a number of patients are non-responders to most treatments.
These are people who are regularly hospitalized and have many
difficulties to lead a normal life. "
Everything starts on ... misunderstanding!
To
improve the quality of life for all these patients, reduce the number
of deaths, or one day cure asthma, researchers are now working to
understand the mechanisms of this disease, decidedly complex. A team from Giga Research, University of Liège has published very interesting results in the magazine PlosOne [1]. They allow to understand the molecular machinery involved in unlikely an asthma attack.
Everything
starts, you might say, on a misunderstanding: a commotion fighting
immune system, so there is no real danger to the body. Everything happens as if our natural defenses overestimated the threat of the enemy. You
breathe in some dust you down on an old mattress or you inhale
fragments of cat hair, and suddenly, it is alert, the body feels
dangerously attacked, beat the recall of the troops and sends cells to the front fenders, namely lymphocytes and eosinophils.
Where does this misjudgment of the immune system? Currently, two assumptions hold the rope. The first on the fact that asthma is primarily a disease of highly developed countries. It seems to suffer more from asthma in the United States and Africa, to take an extreme example. This
could be explained by the fact that the American boy is much less
exposed by his lifestyle and with antibiotics, a range of pathogens that
little African: malaria, tuberculosis and cholera in particular. Too
little stress, the immune system of American small, somewhat in the
manner of trained GIs who are bored in their barracks, would tend to get
a little too fast moving. The immune system of young African, who fights daily against enemies really dangerous to not excite ... one cat hair!
The second assumption is that pollution. A series of substances in our environment would influence how genes are arranged within our cells. To
express genes should not be completely folded on themselves, they must
be "decondensed" accessible to the action of certain molecules in their
cellular environment. Certain
pollutants (eg tobacco) would be to alter the compaction mechanisms of
certain genes, making them more accessible to trigger certain molecular
reactions underlying the asthmatic reaction.
A very complicated dynamic inflammatory
Researchers
are beginning to see a little more clear about the chain of molecular
reactions that cause narrowing of the lumen of the bronchi (inside) and
causes difficulty breathing. "But
to be honest, says Didier Cataldo, whenever we elucidate a mechanism,
it falls on new issues. Molecular dynamics asthma, like all inflammatory
diseases, is very complicated!" And the researcher scribbling
on a sheet the main steps of the reaction: lymphocytes, plasma cells,
mast cells, histamine, eosinophils, leukotrienes ... The latter acting directly on the smooth muscles, which form the wall of the lumen of the bronchi by contracting. This is the bronchial spasm. The pharmacological strategy is to try to interrupt the chain molecular crucial place of the circuit. Corticosteroids, for example, among other act against eosinophils. Another
way to fight against asthma is acting directly on the contraction of
bronchial smooth muscle so on, using bronchodilators.
To
develop new treatments, researchers are trying to solve all the
molecular mechanisms at the origin of asthma, including identifying the
genes that are active in this reaction. Researchers
from the University of Liège work including laboratory mice which were
made asthmatic by exposure to allergenic agents. Their lungs are crushed and researchers are then able to extract the principal components by family proteins, DNA, RNA, etc.. "We
conducted a first study a few years ago to try to find the genes that
are overexpressed in the lungs of asthmatic mice compared to normal
mice, explains Didier Cataldo. Thanks to this study, fourteen thousand
genes studied, we developed a short list of fifteen obviously very involved in the asthmatic response. "
From
this list, researchers can try to block one or the other gene to see if
it reduces or eliminates the asthmatic reaction, for example by using
the strategy of knock-out mice (genetically engineered to express not specific gene). But
in the wake of this first study, researchers Liège GIGA embarked on
another important work: identification in the lungs of asthmatic mice
microRNA. In
a cell, the mRNA molecules are single-stranded ribonucleic acid
resulting from the separation of the two strands forming the spiral DNA.
This is from the RNA molecule that the body produces proteins that are real versatile tools of the cell. The
RNA molecule, to form a protein, is very long (several thousand
nucleotides commonly: ACTG) and originates from the "reading" of a
specific DNA fragment is called a gene. MicroRNAs, as their name suggests, are much smaller. They come from the non-coding part of the genome. In fact, on a DNA molecule, nearly 99% are not used to make proteins and the function of this DNA "silent" is a great mystery. "What
is certain, says Didier Cataldo is that these microRNAs are a mechanism
developed in nature long ago. They are found in all cells of the
eukaryotic type." Very small size, twenty
nucleotides on average, microRNAs have the ability to hybridize (with
the A and C with G T) to a messenger RNA molecule whose sequence
corresponds precisely. When
it clings to a messenger RNA molecule, which recognizes very reliably
by the sequence complementarity, micro-RNA messenger RNA prevents
complete its work of making a protein. "It
is therefore an additional mechanism for control of gene expression
within the cell, says Didier Cataldo., And our study revealed a list of
mRNA that are over or under-expressed instead in the lungs of asthmatic mice. "
In
asthma as in other diseases, research on microRNAs opens new
therapeutic perspectives: the development of micro-RNA that could be
used pharmacologically to control the action of a gene critical in molecular cascade that causes asthma. It is obviously much easier to make a sequence of 20 nucleotides in a sequence which contains thousands. But the only study Liège generated tens of micro-RNA involved in one way or another in asthma. How to choose in this rainforest molecular sequence that will be tested in the laboratory? A
first criterion is the importance of genetic overexpression, whether
this microRNA is two or three times more expressed in the asthmatic lung
hundred times or more. A
second criterion is whether the messenger RNA which binds to the
microRNA is already known in the literature as a crucial area of
molecular sequence responsible for asthma.
"Generally,
explains Didier Cataldo, bioinformatics help us in this work, because
by linking the molecular databases that exist around the world, we can
identify molecular sequences, as they say of pathways in
the jargon, and establish some sort of models to identify therapeutic
approaches. But let's be honest, with this research, we are not patient
tomorrow ".
-
[1]
MicroRNAs profiling in murine models of acute and chronic asthma: a
relationship with targets mRNAs Garbacki N, Di Valentin E, Huynh-Thu VA,
Geurts P, Irrthum A Crahay C, Arnould T, Deroanne C, Piette J, Cataldo D, A. Colige MicroRNAs profiling inmurine models of acute and chronic asthma: a relationship with mRNAs targets.PLoS One. 28 January 2011, 6 (1): e16509.
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