By Lindy McCollum-Brounley
GAINESVILLE, Fla. - Outside, the mercury may be rising, yet you can't seem to warm up; in fact, you might feel downright chilled.
Now University of Florida scientists have found the first evidence to explain why, and it turns out it's an inside job: Certain nerve cells in the body appear capable of transmitting the sensation of cold to the central nervous system without ever coming in contact with the outside environment like their brethren nearer the skin's surface. Instead, these cells are studded with receptors that seem to receive sensory input from hormones, proteins or other biochemical compounds within the body. The finding, published this month in the Journal of Neuroscience, is a step toward better understanding why menopause, depression or fevers sometimes cause chills.
"What we are working to understand is the physiological and pathological roles of these receptors, and why some people may feel cold or pain despite external stimuli," said neuroscientist Jianguo G. Gu, Ph.D., who is affiliated with the UF College of Dentistry and UF's McKnight Brain Institute. "That could explain why it is that you and I can sit in the same space and you will feel comfortable and I may feel cold, yet the environmental stimuli are the same."
Skin is our largest and most versatile organ. Not only is it a 20-square-foot wash-and-wear raincoat for our internal organs, it also sends thousands of impulses to the central nervous system that enable the brain to interpret external conditions. Our skin allows us to find welcome relief in the chill of air-conditioning on hot summer days and compels us to bundle up when the air outside is nippy.
Other scientists have only recently identified the separate hot and cold nerve cell receptors in the peripheral nervous system, those nerves just under our skin that sense external environmental conditions and transmit that information to our central nervous system.
Picture the nerves of the peripheral nervous system laced under the surface of our skin like electrical leads on a circuit board, channeling external sensory information to the central nervous system at the spinal cord, deep in the body. The central nervous system receives this sensory information from the peripheral nerves and forwards it to the brain.
"We have, in this paper, found that, in addition to the cold receptors where you would expect to find them under the skin on the peripheral side of the nervous system, there also are cold receptors on the central side of the peripheral nervous system within the spinal cord," Gu said.
Gu and his colleagues studied the effects cool temperature and menthol, a chemical property of peppermint associated with cooling effects, had on a specific sensory molecule found on the tips of peripheral nerves. To accomplish this, the research team placed central and peripheral nerve cells from rats together in laboratory dishes to mimic the cells' relationship to each other inside the body. Then they exposed the cells to cold and menthol.
"When they are together, just as they do in the body, these neurons make a connection called a synapse that transmits cold sensory information from the peripheral neuron to the central nervous system neuron when stimulated by cold temperature and menthol," Gu said. "We found the cold receptors on the central side of the peripheral neurons responded to the temperature stimuli. What makes this exciting is that the central terminal, or ending, of a peripheral nerve actually expresses the cold and menthol receptors."
This central-side response of the cold receptor to environmental temperature is important because, inside the animal, those nerve cells are never exposed to environmental temperatures. That may mean they are present on the central side to receive stimuli from biochemical substances inside the body.
"The finding that the cold and menthol receptor is present infunctional form at nerve terminals within the spinal cord is potentially quite exciting," said Michael J. Caterina, M.D., Ph.D., a researcher from Johns Hopkins University School of Medicine who is credited with first identifying hot receptors in the peripheral nervous system sensitive to heat and capsaicin, the chemical in hot peppers that makes them hot.
Caterina added that it remains to be seen whether the cold receptor at the spinal cord level is actually functional or if it is just an evolutionary leftover. Even if the latter is true, drugs that target the cold and menthol receptor might still be useful for modifying the spinal processing of sensory information, Caterina said.
"Future studies will help us understand the mechanisms that serve as antagonists for this cold receptor," Gu said. "Right now, we really just don't know how this receptor might function in the central nervous system, but we see all these possibilities."
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UF scientists find enzyme protects cells during gene therapy
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By Melanie Fridl Ross
GAINESVILLE, Fla. - An enzyme instrumental to the body's ability to repair itself appears to also stop a gene therapy virus from damaging a cell once the virus delivers its corrective cargo, University of Florida scientists report today (2/2) in the online edition of the Proceedings of the National Academy of Sciences.
Gene therapy has been heralded as one of medicine's most promising frontiers, but as with any unchartered territory, dangers lurk. A key concern has been whether the viruses used to ferry therapeutic genes into cells to treat diseases such as Parkinson's or diabetes also cause a second, unwanted effect: genetic mutations that ultimately trigger cancer. That fear was heightened last year when two boys with an immune system disorder developed leukemia after undergoing gene therapy in France using a retrovirus.
Now UF researchers say their findings add to mounting evidence that the adeno-associated, or AAV, virus is potentially safer than other gene transport viruses that have been associated with harmful side effects.
"One of the major concerns in gene therapy research is that the insertion of a new gene into the genome of the cell might somehow trigger a new tumor or cancer of some kind," said Terence R. Flotte, M.D., the Nemours eminent scholar and chairman of the department of pediatrics at UF's College of Medicine. "That is a scenario that has been well-established to cause tumors in mice and birds. One of the observations we've had for a long time is that AAV, as compared to other viruses that have been used for gene therapy, doesn't cause any disease that we know of, including cancer. So the question was, is this risk associated with a retrovirus gene therapy vector also present in the case of AAV?"
Flotte pointed out that UF researchers did not set out to directly assess safety issues associated with using AAV, but the study did yield a better understanding of the mechanism by which it works - insight that led them to presume any risk linked to AAV is lower than that posed by other gene therapy methods.
In the early 1980s, study co-author Kenneth I. Berns, M.D., who now directs the UF Genetics Institute, helped lead the effort to modify and patent AAV for use as a vector for transporting the corrective genes used in gene therapy. UF geneticists, led by Flotte, pioneered the first AAV gene therapy trial in patients with cystic fibrosis. UF also produces the world's reference standard AAV vector with National Institutes of Health support.
AAV is attractive to scientists in part because of its unique biology. It is apparently harmless to humans and expresses corrective genes for long periods of time in animal models.
UF scientists studied what would happen when AAV was introduced in cell cultures. They also examined its effects on healthy mice whose cells produced the enzyme known as DNA-dependent protein kinase and on mice with an immune deficiency syndrome whose cells lacked the enzyme. Liver cells were taken from the mice and analyzed to see whether they retained AAV's own genetic material and whether the therapeutic gene had been successfully transferred.
Researchers discovered that once AAV is introduced into a cell, it efficiently transfers the corrective gene it is carrying. But the virus has its own genetic material that could wreak molecular mayhem by seeking to insert itself into a cell's nucleus, if it weren't for the cell's self-repair mechanism, which swings into action. This molecular "fix-it" kit quickly sequesters AAV's own DNA, then handily packs it up into a large new chromosome. In this safe form, the viral DNA rarely invades a cell's own genetic machinery.
"That mechanism - the fact that when AAV enters a cell it turnson DNA repair - creates a scenario where AAV is probably much safer than a retrovirus from the stand point of cancer risk," Flotte said. "This finding is potentially of major significance because there is so much attention on the cancer risk of gene therapy. This is a real direct indication that AAV can get around that."
Researchers noted that mice with a compromised immune system lacked the enzyme, and in some cases the viral DNA did integrate into their cellular genome.That led the scientists to conclude that the enzyme inhibited AAV integration, said Sihong Song Ph.D., the study's lead author and an assistant professor of pharmaceutics at UF's College of Pharmacy.
"So far we think AAV is the safest vector, because this virus itself never causes disease," Song added. "And so far, several clinical trials using this vector have never shown any vector-related side effects."
In some cases, UF researchers said, scientists might actually prefer for a viral vector to incorporate itself into a cell's genetic wiring, and in those instances AAV might not be the best choice, since in many cases it isn't likely to do so.
"If you're going to use a bone marrow stem cell that could beimportant for regenerating some tissue or cell type, then we might want the integrating vector to stay with the cell as the cell repopulates an entire organ or cell type in the body," Flotte said. "Our findings would suggest that under these conditions this kind of vector (AAV) is not ideal. For something where we want to inject a virus directly into the lung, liver, muscle, retina or brain and just have those cells express the gene, then we might be able to do that more safely with this kind of vector - that is our interpretation."
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