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Bench
discovery raises hopes for therapy in spinal cord injuries
Scientists can
regrow severed brain and spinal cord axons in the laboratory,
but something in the adult central nervous system prevents their
regeneration in humans. As a result, paralysis and other disabilities
resulting from brain or spinal cord trauma are irreversible in
most cases. Three separate research teams, including a group
from Yale and Harvard, have identified a gene and its protein
that appear to block axon regeneration. The discovery of what
is termed “Nogo” raises the possibility of developing
a therapeutic means of inhibiting its activity, increasing the
hopes that brain and spinal cord injuries might one day be reversible.
Previous experiments
have shown that the natural adult brain environment contains
one or more substances that inhibit the regrowth of central nervous
system axons, unlike nerve cell connections in other parts of
the body. Three papers published in the January 27 issue of Nature,
including the Yale-Harvard group’s, reported the cloning
of Nogo and identified its activity as an inhibitor present in
the brain and very likely responsible, at least in part, for
the failure of axons to regenerate.
The Yale-Harvard
study showed that the Nogo protein, by itself, stops axon growth
in laboratory conditions. The protein is found only in those
areas of the brain which are most hostile to axon growth.
“Is this
the answer?” asks Stephen M. Strittmatter, M.D., Ph.D.,
associate professor of neurology and of neurobiology, leader
of the Yale team. “We’re pursuing experiments that
will take things to the next step.” These include generating
a mouse model in which the Nogo gene will be “knocked out”
or disabled, and then inducing central-nervous-system injuries
to see if axons regenerate. The Yale members of the group also
are trying to develop a possible blocker for the action of Nogo
and to identify the receptors mediating its activity. |
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The
“taste of temperature” not such an odd notion
What does a
change in temperature taste like? According to a study by Yale
investigators, the same salty, sweet or sour tastes that are
normally caused by food, drink and other chemical substances
on the tongue.
“We’ve
discovered that specific tastes can be produced by temperature
stimulation, just as certain chemicals can evoke only certain
taste qualities,” said Barry G. Green, Ph.D., professor
of surgery in the section of otolaryngology and a fellow of the
John B. Pierce Laboratory, who directed the study. The paper,
which was published in the February 24 issue of Nature,
is the first to show how the brain interprets thermal stimulation
of the tongue. The investigators cooled and warmed various areas
of the tongue under precisely controlled conditions to study
what taste sensations subjects experienced.
Individuals
perceived “thermal taste,” as it is called, differently
on different parts of the tongue. Warming the front of the tongue
induced sweetness and cooling it produced a salty or sour taste,
while chilling the back of the tongue created a sour or bitter
sensation. However, not everyone experiences thermal taste and
the exact temperature conditions needed to produce it are rarely
encountered in daily life.
The close relationship
between temperature and taste qualities suggests that receptors
in the tongue that respond to chemicals have certain properties
that make them vulnerable to specific kinds of temperature change.
This information may provide clues to understanding the nature
of these receptor processes, as well as potential therapies for
when they go awry. |
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Animal
model developed for Type I diabetes
Insulin-dependent,
or Type I, diabetes is one of the most common and potentially
devastating chronic diseases. Yale investigators took a step
toward unlocking the mechanisms behind it by creating an animal
model showing one gene can cause the disease, while another gene
can provide resistance to it. The findings were made when the
researchers induced diabetes in a mouse with HLA-DQ8 in the presence
of the B7 co-stimulatory molecule. HLA-DQ8 is a human gene long
suspected of being a factor in the disease. They also prevented
diabetes from developing in a transgenic mouse expressing the
HLA-DQ6 gene.
Type I diabetes
is an autoimmune disease in which the body produces an immune
reaction that attacks its own tissues, eventually preventing
the pancreas from producing insulin, which is necessary for the
body to metabolize sugars. Researchers have previously shown
in the laboratory that HLA-DQ8 is associated with diabetes. The
study’s lead author, immunologist Li Wen, M.D., Ph.D., assistant
professor of medicine, said: “This is the first time it
has been shown in vivo that HLA-DQ8 causes Type I diabetes and
HLA-DQ6 confers resistance. Not only can we now study the molecular
mechanism in more detail in a living organism, this is also very
important for work in preventing and even curing the disease.”
The study was
published January 3 in the Journal of Experimental Medicine.
Wen and colleagues are now looking further into the roles of
both genes in diabetes. |
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A
new form of Ras is identified
A Yale molecular
biologist in collaboration with a colleague in Korea has identified
a new type of Ras protein, a class of genes known to be involved
in nearly a third of all cancers. Because the new protein is
different from the other known Ras proteins, the finding opens
up a new area of study.
Sankar Ghosh,
Ph.D., associate professor of immunobiology and an associate
investigator in the Howard Hughes Medical Institute, and his
colleague found the new protein, kB-Ras, during studies of NFkB,
a factor involved in relaying genetic information. kB-Ras regulates
the action of NFkB. “What was surprising,” said Ghosh,
“was that other Ras proteins have characteristic mutations
that cause cancer, but kB-Ras has the mutation in its natural
form.” Unlike the others, however, kB-Ras lacks essential
components for traveling to the cell membrane, which would be
necessary for it to cause cancer. The finding was reported in
Science in February.
The scientists
are now studying various aspects of the gene and making an animal
model. “We want to find out if there are mutated states
in which it could become an oncogene,” Ghosh said. |
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A
drug that may reverse memory loss
Short-term,
or working, memory is often lost due to age, mental illness and
long-term treatment with antipsychotic drugs. A Yale study found
that an experimental drug provided long-lasting reversal of memory
loss in primates, offering hope for humans suffering from working
memory loss.
In the study
published in the March 17 issue of Science, Yale investigators
found that even short-term treatment with the experimental drug
ABT-431 reversed memory loss in monkeys that were being administered
haloperidol, an antipsychotic compound that causes loss of short-term
memory in these animals. The principal investigator for the study,
Patricia S. Goldman-Rakic, Ph.D., professor of neurobiology,
neurology and psychiatry said, “What’s remarkable about
this particular drug is that patients would only need to use
it for a short period of time to achieve long-lasting effects.
Experiments at Yale are investigating the cellular and molecular
mechanisms of this drug’s actions and it is not currently
available for clinical application.” |
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Protein plays role
in regulation of dopamine
Researchers at Yale and the Medical College of Georgia have
taken an important step in unraveling the complex molecular interactions
in the brain’s dopamine receptor system. The discovery by
Clare Bergson, Ph.D., formerly at Yale and now at the Medical
College of Georgia, of a new protein in the dopamine signaling
pathway, calcyon, could pave the way for new treatments for mental
illness, including Parkinson’s disease, schizophrenia and
possibly attention deficit hyperactivity disorder.
The protein is named for “calcium on” because it
interacts with one of the known dopamine receptors in the brain,
the D1 receptor, to enhance release of calcium, which increases
dopamine’s activity. Low levels of dopamine activity are
associated with mental illness. The work was done with brain
cells in the laboratory. “The next step,” said Patricia
S. Goldman-Rakic, Ph.D., professor of neurobiology, neurology
and psychiatry, and primary investigator at the Conte Center
for the Neuroscience of Mental Disorders, “is to learn if
calcyon can increase the response of these neurons in the living
animal.” |
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Molecular ‘ZIP coding’
system speeds proteins to their appointed destinations
From brain receptors to hormones, nearly half of the proteins
in the body serve to transport biochemical information from one
cell to another. Yale researchers have now described a major
component of the molecular machinery for reading the “ZIP
code” that guides a protein’s movement from the inside
to the outside of the cells. The findings open up a new window
on evolution and offer possible novel targets for drug discovery.
In a cover story in the February 18 issue of Science,
the study revealed the molecular details of the machinery that
identifies and delivers proteins to their correct destination.
A protein first must be identified for transport, then find the
right target and, finally, be transported through cellular membranes
to its destination. Under the direction of Jennifer A. Doudna,
Ph.D., professor of molecular biophysics and biochemistry and
an associate investigator of the Howard Hughes Medical Institute,
co-investigator Robert Batey, Ph.D., determined the atomic structure
of the protein-RNA complex that recognizes an amino acid ZIP
code tag, or signaling sequence, that identifies proteins to
be transported to the cell membrane for secretion.
This complex, part of the signal recognition particle, or
SRP, was already known to serve a recognition function, but the
discovery suggested a previously unknown and surprising role
for RNA in the direct recognition of the amino acid ZIP code,
or signal peptide, in the protein being identified for transport.
“We think that the RNA and the protein in the SRP work together
to recognize the signal peptide,” Doudna said. “Previously
it’s been thought that the functions of the proteins and
the RNA were separate. Here we are seeing an example of true
molecular collusion.” |
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Preventive factor may
be a cause of heart disease
According to a Yale study, a key immune factor produced by
white blood cells that was thought to prevent hardening of the
arteries may actually cause arteriosclerosis, one of the most
common contributors to potentially lethal heart disease. An interdepartmental
team of surgeons and scientists found that interferon-gamma,
which is produced by white blood cells and was previously believed
to inhibit the processes responsible for arteriosclerosis, increased
blockages in animal models.
The researchers were looking to develop new animal models
to assess human transplantation responses. Heart transplants
frequently result in the greatly accelerated development of arteriosclerosis.
The scientists inserted segments of arteries from pig or human
hearts into the major blood vessel of mice that lacked immune
systems and, as such, could not reject the foreign arteries.
When the mice were treated with injections of pig or human interferon-gamma,
the grafts developed arteriosclerotic lesions. “This observation,”
said team member George Tellides, M.D., Ph.D., assistant professor
of cardiothoracic surgery, “may improve our ability to develop
treatments for arteriosclerosis. Also, we may be able to identify
methods to genetically alter pigs to serve as organ donors of
hearts resistant to arteriosclerosis.” The study was published
in the January 13 issue of Nature. |
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A new twist on protein
folding
As disordered, one-dimensional strings of amino acids, proteins
cannot carry out their essential work in cells. In order to function,
these complex molecules must first fold into stable, three-dimensional
structures.
It has long been assumed that proteins must have an oily core
to reach a stable configuration. But Donald M. Engelman, Ph.D.,
professor of molecular biophysics and biochemistry, and Shoei
Koide, Ph.D., a collaborator at the University of Rochester Medical
Center, have shown that the process can indeed vary. Their findings
represent a major shift in the previously standard view of protein
folding.
Protein folding is a subject of intense scientific interest,
because incorrect folding is a factor in chronic diseases including
adult-onset diabetes and Alzheimer’s disease. Medical researchers
hope to understand protein folding not only to develop diagnostic
tools and therapies for diseases caused by failure of the process,
but to understand the information in the genome.
Previously it was believed that proteins organize themselves
by first forming a long, stringy polypeptide that then collapses
into a compact shape by separating its oily parts from water.
At that point, the proteins organize themselves into functional
structures. In an article that appeared in the January 27 issue
of Nature, the two scientists reported that they had modified
a protein in such a way that it organized itself without use
of the hydrophobic, collapsing mechanism. “There is at least
one alternative way of folding a protein without this feature
that everyone thought was the key,” said Engelman. “This
is a paradigm shift.” |
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Why are we so tasty to
bugs? A genetic basis emerges in the lab
Insects devour up to 40 percent of the world’s crops
and spread disease to hundreds of millions of humans and livestock
every year. Controlling pests has proven difficult at best, and
current methods often have significant environmental side effects.
The discovery of insect taste receptor genes by Yale scientists
gives researchers new tools for understanding insect taste systems,
and possibly for developing novel means of pest control.
John R. Carlson, Ph.D., professor of molecular, cellular and
developmental biology, directed a research group that, for the
first time, has identified insect taste receptor genes-nearly
40 for the fruit fly Drosophila. The discovery, published
in Science in March, follows up on Carlson’s study
detecting insect odor receptors that was published last year.
The finding could lead both to a fundamental understanding about
the physiology of taste systems and to development of nontoxic
compounds to apply to crops, livestock and humans that would
taste repulsive to the insects. |
