Promising compounds and potential drug targets found
Monday, 10 March 2008
Scientists using a new drug screening method in Drosophila (fruit flies), have identified several drugs and small molecules that reverse the features of fragile X syndrome – a frequent form of mental retardation and one of the leading known causes of autism. The discovery sets the stage for developing new treatments for fragile X syndrome.
The results of the research by lead scientist Stephen Warren, PhD, chair of the Department of Human Genetics at Emory University School of Medicine, are published online in the journal Nature Chemical Biology.
Dr. Warren led an international group of scientists that discovered the FMR1 gene responsible for fragile X syndrome in 1991. Fragile X syndrome is caused by the functional loss of the fragile X mental retardation protein (FMRP). Currently there is no effective drug therapy for fragile X syndrome, and previously no assays had been developed to screen drug candidates for the disorder.
During the past 17 years, intense efforts from many laboratories have uncovered the fundamental basis for fragile X syndrome. Scientists believe FMRP affects learning and memory through regulation of protein synthesis at synapses in the brain. One leading view, proposed by Dr. Warren and colleagues, suggests that over stimulation of neurons by the neurotransmitter glutamate is partly responsible for the brain dysfunction resulting from the loss of FMRP.
In their current experiment, Emory scientists used a Drosophila model lacking the FMR1 gene. These fruit flies have abnormalities in brain architecture and behaviour that parallel abnormalities in the human form of fragile X syndrome. When FMR1-deficient fly embryos were fed food containing increased levels of glutamate, they died during development, which is consistent with the theory that the loss of FMR1 results in excess glutamate signalling.
The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. The scientists’ uncovered nine molecules that reversed the lethal effects of glutamate, using this screening method.
The three top identified compounds were known activators of GABA, a neural pathway already known to inhibit the effects of glutamate. In the study, GABA reversed all the features of fragile X syndrome in the fruit flies, including deficits in the brain's primary learning centre and behavioural deficits. The screening also identified other neural pathways that may have a parallel role in fragile X syndrome and could be targets for drug therapy.
"Our discovery of glutamate toxicity in the Drosophila model of fragile X syndrome allowed us to develop this new screen for potential drug targets," notes Dr. Warren.
"We believe this is the first chemical genetic screen for fragile X syndrome, and it highlights the general potential of Drosophila screens for drug development. Most importantly, it identifies several small molecules that significantly reverse multiple abnormal characteristics of FMR1 deficiency. It also reveals additional pathways and relevant drug targets. These findings open the door to development of effective new therapies for fragile X syndrome."
First author of the article was Shuang Chang, postdoctoral student in Emory's Department of Human Genetics. Other authors included Steven M. Bray and Peng Jin from Emory, Zigang Li from the University of Chicago and Daniela C. Zarnescu from the University of Arizona.
The research was supported by the National Institutes of Health, the Fragile X Research Foundation, and the Colonial Oaks Foundation.
Dr. Warren is chair of the scientific advisory board for Seaside Therapeutics, which is developing drugs for fragile X syndrome.
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ZenMaster
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Monday, 10 March 2008
Drosophila Drug Screen for Fragile X Syndrome
Sunday, 9 March 2008
Toxins In Cigarette Smoke Prevent Stem Cells From Becoming Cartilage
Toxins In Cigarette Smoke Prevent Stem Cells From Becoming Cartilage Monday, 03 March 2008 A toxic pollutant spread by oil spills, forest fires and car exhaust is also present in cigarette smoke, and may represent a second way in which smoking delays bone healing, according to research presented today at the annual meeting of the Orthopaedic Research Society in San Francisco. In 2005, researchers from the University of Rochester Medical Center identified one ingredient in smoke, nicotine, that delays bone growth by influencing gene expression in the two-step bone healing process: stem cells become cartilage; cartilage matures into bone. In the current study, some of the same researchers found that a second smoke ingredient, the polyaromatic hydrocarbon benzo(a)pyrene (BaP), also slows bone healing, but in a different way. Smoking has been shown to delay skeletal healing by as much as 60 percent following fractures. Slower healing means a greater chance of re-injury and can lead to chronic pain and disability. The obvious solution is for smokers to quit when they get hurt, but studies show that just 15 percent can. “Our results provide the first evidence that BaP prevents stem cells from becoming cartilage cells as part of healing,” said Regis J. O'Keefe, M.D., Ph.D., chair of the Department of Orthopaedics and Rehabilitation at the Medical Center and a study investigator. “These findings extend our understanding of the impact of cigarette smoke on a process that is critical to fracture repair. Perhaps down the road we will be able to speed bone healing among smokers in more than one way.” Study Details Gene expression is the process by which instructions encoded in genes are followed for the building of proteins, the workhorses that make up the body’s organs and carry its signals. In the current study, polymerase chain reaction (PCR), a technique that measures gene expression levels, revealed the genetic changes caused by exposure to BaP in mouse stem cells. Among the many factors that influence gene expression are transcription factors, proteins designed to direct genes to create more or less of a protein. One such factor is Sex Determining Region Y-box 9 (SOX-9), required for the transition of stem cells into cartilage cells. The PCR results show that BaP in cigarette spoke interferes with SOX-9 expression in mesenchymal stem cells, blocking their conversion into cartilage cells. When this group of stem cells is free to differentiate, the newly formed cartilage cells immediately begin manufacturing collagen 2, the tough, fibrous protein framework for cartilage. Along with interfering with SOX-9, BaP was also found to reduce levels of type II collagen gene expression. Past studies had shown that stem cells involved in cartilage formation contain proteins known to react with BaP called aryl hydrocarbon receptors. The current results suggest that BaP binding with these receptors may suppress SOX-9 activity, reducing the number of stem cells that turn into cartilage cells and the amount of collage produced. No one knows what such receptors are doing in these cells in the first place, but one theory has it that they signal cellular machinery to metabolize toxins. The study compared the effect of BaP versus that of cigarette smoke extract, a substance representing all the ingredients in cigarette smoke. The hope was to confirm BaP as the specific cause of the observed effect on SOX-9. Results indeed suggest BaP alone may responsible for this specific mechanism of healing delay, since its effect was equal to the extract. In addition measuring gene expression levels, researchers also conducted tests to show the effect of BaP visually. When newly differentiated cartilage cells begin to produce collagen in a culture dish, little mounds or nodules of collagen can be visualized using a stain. Staining experiments captured images showing BaP to “completely inhibit” collagen nodule deposition. Along with O’Keefe, the Medical Center effort was led by Ming Kung, Donna Hoak, HsinChiu Ho, Edward Puzas and Michael Zuscik, all within the Department of Orthopaedics at the Medical Center. "Smoking reduces the rate at which the two sides of a fracture come together," said Michael Zuscik, Ph.D., associate professor in the Department of Orthopaedics and Rehabilitation at the Medical Center. "We believe this new research will establish for the first time the mechanisms by which polyaromatic hydrocarbons interfere with the healing process.” ......... ZenMaster
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Giant Panda Genome to Be Sequenced
Giant Panda Genome to Be Sequenced
Thursday, 06 March 2008
BGI-Shenzhen is pleased to announce the launch of the International Giant Panda Genome Project. This announcement follows on the heels of the Panda Genome workshop held on January 21–22, 2008, in Shenzhen, China.
Dr. Hongmei Zhu, a scientist from BGI-Shenzhen, stated that, "The goal of this project is to finish the sequencing and assembling of the draft sequence within six months."
The giant panda is a much loved animal all over the world and is considered a symbol of China, as illustrated by its being one of the mascots for the upcoming Olympics in Beijing. The excitement surrounding the launch of this ambitious project, however, has been built around how this new genomic information will have extensive impact in numerous scientific areas — from ecology to evolution to sequencing technology. Such data will aid in understanding the genetic and biological underpinnings of this unique species, especially with regard to its very specific niche in the environment and the molecular mechanisms of its evolution. Of special interest is that these data will be extremely useful for protecting and monitoring this endangered species and will provide information on the impact of captive breeding. In addition, it will have considerable use in controlling diseases that could devastate these fragile populations. Because scientists will be utilizing the latest Now-Gen sequencing technology to carry out this research, this project will also have far-reaching implications for promoting advances in sequencing tools and techniques.
“The most noteworthy aspect of the project,” said Oliver Ryder of the San Diego Zoo’s Center for Conservation and Research for Endangered Species (CRES) and a participant at the January workshop, “is that it is the first genome project to be undertaken specifically to gather information that will contribute to conservation efforts for an endangered species. The giant panda is a global conservation symbol and deserving of such an effort.”
Ya-Ping Zhang, a member of the Chinese Academy of Sciences and Director of the Kunming Institute of Zoology at the Chinese Academy of Sciences, put equal emphasis on the evolutionary impact of these studies, saying, “the genome project will help scientists to understand the genetic basis for giant panda adaptation to its special diet and behavioral style, and to reveal the history of population isolation and migration.”
Often referred to as a living fossil, given evidence that its ancestors existed in China over 8 million years ago, the giant panda has been the focal point of many research projects. So far, however, little research has been done on a genomic scale. The giant panda has a genome size of about 3 Gb, which is approximately the same size as the human genome, and is thought to have 20,000–30,000 genes. Taxonomy and genetic studies indicate that the giant panda is most closely related to bears, not to raccoons as was once considered, given their unique physical characteristics.
The Giant Panda is the logo and flagship species for the World Wide Fund for Nature (WWF), China. Zhiyong Fan, Species Program Director of the WWF-China, made comments based on the importance of protecting the panda in the wild:
“The project is a really ambitious. Its contribution to wild panda conservation has been discussed in the workshop. We are looking forward to its effort”.
Dr. Lin He, a member of the Chinese Academy of Sciences who works at both Shanghai Jiao Tong University and Fudan University, noted that the panda sequence obtained from this project will greatly benefit our understanding of the reduced fecundity in pandas when living under certain environmental conditions. This is a major issue for breeding programs that are carried out to strengthen the panda species as a whole. Dr. Lin He also raised an important point about how this sequence will further aid in learning about the interaction between genetics and the environment, and their impact on the physiology and pathology of the panda.
The panda to be sequenced for the Giant Panda Genome Project will be chosen from the Chengdu and Wolong breeding centers. In addition to producing a high quality genome sequence, the researchers will do a survey of the genetic variations in the panda population. The fine map of the panda’s genome and the transcriptome studies will provide an unparalleled amount of information to aid in understanding both current and past status of the species, including historical population size, current levels of inbreeding, precise estimates of gene-flow, and past connectedness between the two different mountain-top giant panda populations.
In addition to researchers at BGI-Shenzhen, the current participants in this project consist of scientists from all around the globe: including researchers from the Kunming Institute of Zoology at the Chinese Academy of Sciences; the Institute of Zoology at the Chinese Academy of Sciences (Beijing); Chengdu Research Base of Giant Panda Breeding; the China Research and Conservation Center for the Giant Panda (Wolong); the Beijing Institute of Genomics, the Chinese Academy of Sciences; Beijing Genomics Institute (BGI); BGI-Hangzhou; the University of Alberta (Canada); Cardiff University (UK); Fudan University (Shanghai); Sichuan University; Southeast University (Nanjing); Sun Yat-Sen University (Guangzhou); the University of California at Berkeley; the University of Copenhagen; the University of Hong Kong; the University of Washington (Seattle); the World Wide Fund for Nature, China; and the Zoological Society of San Diego.
BGI-Shenzhen also announced the First Asian Genome project last October and participated in the 1000 genomes project this January.
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ZenMaster
For more on stem cells and cloning, go to CellNEWS at
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