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Probing the Body's Protective Inner Barriers
Between the blood and the tissues of all our organs — from our brains,
lungs and hearts to the organs of the immune system — our bodies maintains
a careful balance of immune cells, fluids and countless molecules. When that
balance is disrupted, it can cause serious illness, such as when fluid accumulates
in the lungs or when lymph organs release immune cells that attack the body's
own tissues, as in multiple sclerosis and other autoimmune diseases. A team of
experts funded by NIH has now developed a chemical tool that allows scientists
to manipulate control of the passage of substances between these barriers. Altering
the barriers between the blood and tissues may one day prove an effective way
to prevent and treat illnesses of this kind.
The team of researchers, led by Dr. Hugh Rosen of The Scripps Research Institute,
focused on the S1P1 receptor system. These receptors open and close
molecular "gates" on
biological barriers such as the lining of blood vessels, where the exchange of
substances between blood and tissues occurs, and the tissues of lymph organs,
which produce and regulate the passage of lymphocytes (the main cells of the
immune system) into the bloodstream.
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| Barriers regulate the release of immune cells like this
one into the bloodstream. Image from Dr. Triche, courtesy of NIH’s
National Cancer Institute. |
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The researchers searched for published studies on compounds that block the S1P1
receptor and synthesized a chemical blocker of their own, hoping that it would
promote the passage of substances through the barriers of the vascular and immune
systems. Paired with a previously known activator of the S1P1 receptor to counter
the effects of the chemical blocker, they went on to investigate the effects of
these compounds in mice. They focused on two different biological barriers among
the many on which S1P1 receptors are found: blood vessel walls and lymph organs.
Their study was posted online July 9, 2006, in Nature Chemical Biology.
The compound the researchers synthesized effectively blocked S1P1 receptors.
Using the two chemical compounds together, the researchers were able to reversibly
manipulate these molecular gates in living mice. They found, however, that the
blood vessel and immune-system tissues differed in the levels of these compounds
at which they responded — a reminder of how complex a challenge it will
be to develop therapeutic approaches using this strategy.
This new
chemical
probe is among the first developed by scientists working within NIH's
Molecular Libraries Screening Centers Network (MLSCN). The MLSCN has established
a collection of over 100,000 chemically diverse small molecules for use as chemical
probes in basic research. This study is the latest to illustrate the success
of this approach.
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