This is the twice-per-month electronic newsletter for basic, preclinical and translational research news related to the Johns Hopkins School of Medicine. Please forward freely. Direct comments or questions to Joanna Downer, PhD, in the Office of Corporate Communications (410-614-5105, jdowner1@jhmi.edu).
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IN THIS ISSUE:
RESEARCH HIGHLIGHTS:
+ New Tool Reveals Molecular Signature of Cancer and HIV
+ Genetic Cause of a Cystic Fibrosis-Like Disease Identified
+ Growth Factor Is Behind Heart Problems in Marfan Syndrome
+ Chromosome 1 Genes Behind "Essential Hypertension"
+ "Toolkit" Developed for Functional Profiling of Yeast Genes
NEWS BRIEFS:
Ulatowski To Head Anesthesiology
Funding for Prostate Cancer Research
HONORS AND AWARDS:
Sheridan, Chang Get ASHG Awards
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Do you have an interesting research finding about one month from publication or presentation? Send manuscripts to Joanna Downer at jdowner1@jhmi.edu or fax to 410-614-8951. Information about awards and honors received by laboratory personnel and others is welcomed also.
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RESEARCH HIGHLIGHTS:
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10/26/04
New Tool Reveals Molecular Signature of Cancer and HIV
Scientists have designed a new molecular tool, dubbed "LigAmp," to pinpoint DNA mutations among thousands of cells. Preliminary studies in a small number of cell lines and body fluids show the ultra-sensitive test may help detect microscopic cancer and HIV drug resistance.
"Other molecular tests make it very difficult to locate a mutation in a particular cell surrounded by thousands of other cells that don't have the mutation," says James Eshleman, MD, PhD, associate professor of pathology and of oncology and associate director of the DNA Diagnostic Laboratory. "LigAmp essentially filters background 'noise' caused by normal cells and reveals specific mutations."
The researchers say that sensitive tests to locate mutations could identify cancer in patients at high risk for the disease. Such tests could even help detect a recurrence of cancer by monitoring whether the number of mutations rises above a predetermined threshold value.
The Hopkins team also tested the mutation-finder on blood samples from a handful of patients with HIV. The technique was able to locate DNA mistakes in the virus itself that make it resistant to certain antiretroviral drugs. Results of analyses of the new test are published in the November issue of Nature Methods, a new journal from the Nature Publishing Group.
http://www.hopkinsmedicine.org/Press_releases/2004/10_26_04.html
Nature Methods Nov. 2004;1(2):141-147.
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nmeth/journal/v1/n2/abs/nmeth713.html
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10/28/04
Genetic Cause of a Cystic Fibrosis-Like Disease Identified
Researchers from the McKusick-Nathans Institute of Genetic Medicine and elsewhere have identified the genetic underpinnings of a condition whose symptoms overlap those of cystic fibrosis.
Cystic fibrosis (CF) is characterized by cellular problems in the transport of chloride and sodium, which creates infection-harboring mucus build-up in the lungs, and is caused by mutations in a gene called CFTR. Because of sodium's role in CF, the researchers decided to see if genes for a sodium channel (specifically epithelial sodium channel, or ENaC) might harbor disease-causing mutations in some people with CF-like disease but no CFTR mutations.
By sequencing the three genes that encode the three parts of this sodium channel in samples from 23 patients, graduate student Molly Sheridan and her colleagues discovered three disease-causing mutations. Sheridan presented the findings Oct. 28 at the annual meeting of the American Society of Human Genetics in Toronto.
"One of the mutations we found in the sodium channel genes rendered the channel nonfunctional when we tested it in the lab, and we expect based on sequence information that the other two mutations we identified would also disrupt the channel's function," says Sheridan, who won the society's Predoctoral Clinical Research Award for the work.
http://www.hopkinsmedicine.org/Press_releases/2004/10_28a_04.html
Search for Program Number 51
http://www.ashg.org/genetics/ashg04s/index.shtml
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10/28/04
Growth Factor Is Behind Heart Problems in Marfan Syndrome
Marfan syndrome has long been tied to mutations in a gene called fibrillin-1, but Hopkins researchers now report that the well-known protein transforming growth factor beta (TGF-beta) is directly responsible for the syndrome's deleterious effects on heart valves.
All people with Marfan syndrome have mutations in one copy of their fibrillin-1 gene that reduces the amount of fibrillin-1 protein that cells can make. Unfortunately, that knowledge has proved diagnostic but not therapeutic. However, Hopkins researchers Enid Neptune, MD, Harry (Hal) Dietz, MD, and their colleagues discovered in 2003 that fibrillin-1 deficiency in mice heightens activation of TGF-beta, which directly causes lung problems that lead to emphysema.
Now, Harvard medical student Connie Ng, Dietz and colleagues report that excessive TGF-beta activity is also behind problems with the heart's mitral valve in mice with Marfan syndrome. In experiments with mice missing fibrillin-1, the researchers found that excessive TGF-beta activity was present at the locations of valve distortion. Importantly, blocking TGF-beta's activity in young mice prevented the deadly damage from occurring.
Ng conducted the research during her year as a Sarnoff fellow working in Dietz's lab at Hopkins and presented the findings Oct. 28 at the annual meeting of the American Society of Human Genetics. She was a semifinalist for a Predoctoral Basic Research Award from the society.
http://www.hopkinsmedicine.org/Press_releases/2004/10_28a_04.html
Search for Program Number 75
http://www.ashg.org/genetics/ashg04s/index.shtml
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10/28/04
Chromosome 1 Genes Behind "Essential Hypertension"
Johns Hopkins researchers have discovered that a region of chromosome 1 contains genes that contribute to "essential hypertension," or cases of high blood pressure that appear without a predisposing condition, such as kidney disease.
Such mysterious cases of high blood pressure are thought to stem from problems with the kidney's normal balancing of sodium in the blood, but genetic contributors to this common condition are unknown. Postdoctoral fellow Yen-Pei Christy Chang, PhD, and her team studied samples from 1,875 people representing 585 families. Detailed genetic analysis linked the condition to a region of chromosome 1 that contains hundreds of genes.
"By using information from the Human Genome Project and conducting more in-depth genetic analysis of this region, we narrowed down the likely genes to approximately 30," says Chang, who received a Postdoctoral Clinical Research Award from the American Society of Human Genetics for this work and presented the research at the society's annual meeting Oct. 28. "Looking even closer, we've found significant and consistent association of disease with variants of just three genes, quite a manageable number to investigate further."
One of the three genes identified plays a known role in the kidney's absorption of sodium, and the other identified genes are likely to affect blood vessels' ability to react to changes in blood pressure, the researchers say.
http://www.hopkinsmedicine.org/Press_releases/2004/10_28a_04.html
Search for Program Number 129
http://www.ashg.org/genetics/ashg04s/index.shtml
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11/4/04
"Toolkit" Developed for Functional Profiling of Yeast Genes
Johns Hopkins researchers have built a powerful "toolkit" designed to quickly uncover how yeast's genes interact with each other.
The toolkit, described in the Nov. 5 issue of Molecular Cell, combines techniques developed by the Hopkins researchers and others. The toolkit starts with a collection of almost 6,000 yeast strains, each missing a different gene, and allows researchers to rapidly identify genes whose coupled elimination kills the yeast.
The researchers dubbed the toolkit dSLAM, for diploid-based synthetic lethality analysis on microarrays. "Diploid" reflects the second set of genes added by postdoctoral fellow Xuewen Pan, PhD, to the yeast mutants to prevent the creeping genetic impurity common in slow-growing haploid strains. "Synthetic lethality" refers to genes that only kill the yeast if missing in combination.
"With the toolkit, we study all the yeast mutants simultaneously, which is made possible by using genetic 'barcodes' and a special barcode-based microarray to distinguish the strains after an experiment," says Jef Boeke, PhD, professor of molecular biology and genetics and director of the HighThroughput Biology (HiT) Center in Hopkins' Institute for Basic Biomedical Sciences.
When applied to synthetic lethality experiments already tested by other methods, the new technique missed fewer of the known gene interactions and provided more consistent results than older techniques, the research team reports.
http://www.hopkinsmedicine.org/Press_releases/2004/11_4_04.html
Mol Cell 5 Nov. 2004;16(3):487-496.
http://www.molecule.org/content/article/fulltext?uid=PIIS1097276504005878
http://dx.doi.org/10.1016/j.molcel.2004.09.035
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NEWS BRIEFS:
Ulatowski To Head Anesthesiology -- John Ulatowski, MD, PhD, a world-renowned expert on cerebral blood flow and oxygen delivery in the brain, is the new director of the Department of Anesthesiology and Critical Care Medicine and the new anesthesiologist-in-chief of The Johns Hopkins Hospital. His ongoing research includes the development and application of non-invasive techniques for monitoring brain function in the intensive care unit, fluid management and sedation in patients with brain injury, use of novel oxygen carriers in blood, and new techniques and therapies for stroke.
http://www.hopkinsmedicine.org/Press_releases/2004/11_02a_04.html
Funding for Prostate Cancer Research -- Funding is available to support multidisciplinary research in prostate cancer through the Patrick C. Walsh Prostate Cancer Research Fund and the Johns Hopkins SPORE program. Awards of $50,000 to $100,000 for up to 2 years are available to fund career development and developmental research programs (pilot projects). The deadline for applications is Friday, Jan. 7, 2005.
http://prostatecancerprogram.onc.jhmi.edu/
HONORS AND AWARDS:
Sheridan, Chang Get ASHG Awards -- Molly Sheridan and Christy Chang, PhD, received research awards from American Society of Human Genetics at the society's annual meeting, held in late October in Toronto. Sheridan, a doctoral candidate in the Cellular and Molecular Medicine graduate program, received the Predoctoral Clinical Research Award for her work, conducted in the laboratory of Garry Cutting, PhD, professor in the McKusick-Nathans Institute of Genetic Medicine. Chang, a postdoctoral fellow working with Aravinda Chakravarti, director of the institute, received the Postdoctoral Clinical Research Award. Connie Ng, a Harvard medical student, was a semi-finalist for the Predoctoral Basic Research Award for work conducted with Hal Dietz, MD. Their research projects are described above and at http://www.hopkinsmedicine.org/Press_releases/2004/10_28a_04.html
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--JHMI--
