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RESEARCH BREIFS
Molecule Flips Master Switch for Growth of Nerve Cell AxonsA major challenge for neuroscientists lies in coaxing nerve cells to regenerate their connections after injury to the brain or spinal cord. Recently, a group led by Larry Benowitz, HMS associate professor of neurosurgery at Children's Hospital, discovered that inosine, a small molecule normally found in low levels in most cells, can stimulate nerve cells to do just that. The work, published in the Nov. 1 Journal of Neuroscience, demonstrates inosine's role in activating a "master switch" enzyme that controls the molecular program for axon growth. "What was surprising about these results," said Benowitz, "is that we knew from previous studies that there is a whole set of genes that are commonly activated when nerve cells are forming their connections. However, we didn't know whether the expression of these genes was controlled through separate pathways that are activated by different growth factors, or whether there was a master switch, onto which different signals converge to control an entire constellation of so-called 'growth-associated proteins.' Our findings indicate that the effects of multiple growth factors converge upon a single enzyme which, in turn, regulates this whole constellation of genes." Growth factors act to overcome the suppression of axon growth. But inosine may be capable of eliminating the need for such factors. Benowitz and his colleagues are working on isolating the gene encoding the enzyme upon which inosine works. NIH Panel Outlines Optimal Longterm Treatment for PKUA consensus panel convened by the National Institutes of Health, which included HMS researchers, recently addressed a longstanding difference of opinion about treating the metabolic disorder phenylketonuria (PKU) and concluded that sufferers should, indeed, continue dietary modification after early childhood. Affecting one of every 15,000 infants in the U.S., PKU usually results from a deficiency of the enzyme phenylalanine hydroxylase, and can cause mental retardation and other medical problems if left untreated. The current treatment involves excluding high protein foods, such as meat, milk, eggs, and nuts, since all protein contains phenylalanine. Wheat products also are off limits. Foods that are phenylalanine-free are added to provide nutrients lost to these excluded proteins. The panel, which met at the NIH Consensus Development Conference on PKU: Screening and Management on Oct. 16 to 18, stressed that dietary control of the disease is only one component of a lifelong treatment program. Other precautions include frequent blood tests, daily dietary logs, and regular, frequent visits to a PKU clinic. Experts discussed research findings on PKU epidemiology and genetics, screening strategies, and treatment regimens. Harvey Levy, HMS associate professor of pediatrics at Children's Hospital, spoke of the need to implement the latest screening technologies such as tandem mass spectrometry, which is more sensitive and reliable than standard techniques. Susan Waisbren, HMS associate professor of psychology at Children's Hospital, also spoke during the conference, addressing issues relating to psychosocial factors and dietary adherence with respect to maternal PKU. Panelists also considered potential nondietary treatments for PKU. These include the development of drugs to break down phenylalanine and gene therapy to replace the missing enzyme in PKU patients. Drug Use Up Among College StudentsMarijuana and other illicit drug use is on the rise in U.S. colleges, according to a study by HSPH researchers reported in the November Addiction. In 1993, 1997, and 1999, self-reports from more than 14,000 students each year at 119 four-year colleges demonstrated the rise. Measurements included marijuana and other illicit drug use in the past 30 days and in the past year, cigarette use, drinking behavior, and age of initiation of smoking, drinking, and using marijuana. Henry Wechsler, director of the College Alcohol Studies Program and senior author of the paper, and his colleagues found that marijuana use had increased among most types of student and at almost all types of college, indicating a significant national pattern. The prevalence of past-30-day marijuana use rose from 12.9 percent to 15.7 percent between 1993 and 1999, and almost all of this change occurred by 1997. Although rates of drug use had stabilized at the end of the decade, no significant decreases had been observed. Use of other illicit drugs, such as crack cocaine, barbiturates, amphetamines, and opiate-type drugs, followed the same trend, rising between 1993 and 1997, then changing little between 1997 and 1999. Results from the self-reports showed that 34 percent of past-30-day marijuana users began to use the drug regularly at or after the age of 18, later than for cigarettes. The authors suggest this indicates that college is a time of experimentation with marijuana to a greater degree than with tobacco and that college is the time when many students become regular users. The HSPH team's data also show that 91 percent of students who used marijuana in the past 30 days used other illicit drugs, smoked cigarettes, or engaged in binge drinking. According to Wechsler, "Prevention efforts aimed at illicit drug use should be stepped up and tied to those already in place for binge drinking and cigarette use. Results of this study demonstrate the need for drug abuse prevention programs in the secondary schools as well as in college to prevent experimental illicit-drug users from becoming regular users." Patterns Found in Gene Transcription Response to DNA DamageResearchers at HMS and HSPH now have new information on patterns of transcription regulation in response to DNA damage. Their work, reported in the November Molecular and Cellular Biology, looked at the transcriptional responses of Saccharomyces cerevisiae (brewers' yeast) to alkylating agents, oxidizing agents, and ionizing radiation. Through computational analysis, Leona Samson, HSPH pro-fessor of toxicology, and her colleagues discovered common sequence motifs in promoter re-gions of responsive genes. Their analyses also revealed that transcription of some genes for protein degradation and for DNA repair is modulated by the proteasome-associated protein, Rpn4p. These genes are coordinately regulated by Rpn4p due to a shared regulatory sequence motif up-stream of their coding regions. The Rpn4p binding site was only one of nine sequence motifs identified upstream of the damage-responsive genes. Of the remaining eight motifs, four are known to be bound by previously characterized transcription factors, and four warrant further investigation. The authors say that it will be important to determine the relative importance of each component in protecting against the cytotoxic and mutagenic effects caused by damaging agents such as those used in the study. —Briefs by Tracy Hampton |
