Department News

Structure and function of photolyase and in vivo enzymology - 50th anniversary

ahc — 2008-08-06T14:35:10Z

Dr. Aziz Sancar, Professor of Biochemistry and Biophysics, has dedicated his recent Journal of Biological Chemistry publication to Dr. Claud S. Rupert, his PhD advisor. This paper signifies the 50th anniversary of the discovery of photolyase by Dr. Rupert and his colleagues, an event marking the beginning of the DNA repair field. This anniversary coincides with Dr. Rupert's 90th birthday. Congratulations to all!

Yi Zhang receives the first Battle Distinguished Cancer Research Award

ahc — 2008-07-16T13:50:09Z

The award, established last year by the Battle Foundation of Rocky Mount, recognizes exceptional cancer research at the medical school and comes with a $25,000 prize. The Battle Award fund is a permanent endowment held by The Medical Foundation of North Carolina, Inc.

Zhang, a member of the UNC Lineberger Comprehensive Cancer Center, is an internationally recognized scientist in the area of chromatin, a genetic material. He received the Gertrude Elion Award in 2003 from the American Association of Cancer Research and is a Howard Hughes Medical Institute investigator.

Zhang and his colleagues study how DNA is packaged in different cell types into chromatin. The differences in chromatin affect almost every cellular process from gene expression through the shape and differentiated function of cells and tissues. Chromatin dynamics help explain why nerve cells and skin cells – which have the exact same DNA – differ in shape, size and capabilities. When the enzymes that control chromatin are deranged, cancer can develop.

Zhang’s lab has discovered and characterized many of the proteins that regulate chromatin structure. A testament to the high impact of his work came recently from the research information company, Thomson Scientific, which ranked Zhang 7th worldwide in numbers of high impact citations in the area of molecular biology and genetics.

Hyman L. Battle (1896-1972) established the Battle Foundation in 1946. His grandfather, Kemp Plummer Battle, was an early president of UNC-Chapel Hill.

Lineberger contact: Dianne Shaw (919) 966-5905, dgs@med.unc.edu
News Services contact: Patric Lane, (919) 962-8596, patric_lane@unc.edu

Scott Lujan Awarded the First Annual "Diane Harris Leadership Award"

ahc — 2008-06-06T20:05:32Z

Scott Lujan has been awarded the first annual Diane Harris Leadership Award for his exemplary research, education and or public service as a graduating doctoral student. The department elected to create the new award in honor of Diane Harris, who retired last year after 20+ years as student services manager, a position she held with great dedication and loyalty. Scott trained in the lab of Matthew Redinbo and focused his research on bacterial conjugation and targeted drug design. He graduated this year with a PhD in Biochemistry and Biophysics and is currently employed at the NIEHS in RTP, NC.

Clumps of red and white blood cells may contribute to sickle cell disease

ahc — 2008-06-06T16:30:30Z

It’s long been known that patients with sickle cell disease have malformed, “sickle-shaped” red blood cells – which are normally disc-shaped – that can cause sudden painful episodes when they block small blood vessels.

Now, researchers at the University of North Carolina at Chapel Hill School of Medicine have shown that blood from sickle cell patients also contains clumps, or aggregates, of red and white blood cells that may contribute to the blockages.

The study, published on-line April 18 in the British Journal of Haematology, marks the first time that aggregates made up of red blood cells and white blood cells have been found in whole blood from sickle cell patients. The study also shows how the red and white blood cells adhere to one another: the interaction is mediated by a particular protein, integrin alpha four beta one.

First author Julia E. Brittain, Ph.D., a research assistant professor in the medical school’s department of biochemistry and biophysics, said further study could lead to new treatments for the disease. “If the blockages are caused by these chunks of aggregates that are circulating in the blood, and we know how the aggregates are sticking together, we potentially could design drugs to disrupt the aggregates so that they pass through the blood vessel more freely,” she said.

Normal red blood cells don’t interact with white blood cells. But Brittain first showed in lab tests with isolated cells that young red blood cells (reticulocytes) would interact with white blood cells and form aggregates with them. Then, she looked for such clumps in blood samples from 14 people with sickle cell disease. All the patient samples studied had clumps, though some had only a few, while others had thousands. She didn’t see clumps in samples from patients without sickle cell disease.

Brittain said other researchers may have disrupted the aggregates because blood collection tubes usually contain an anticoagulant that ties up calcium, which often plays a role in cell adhesion. She saw the aggregates only when she used an anticoagulant that doesn’t remove calcium.

Brittain and her colleagues plan further study of the phenomenon, including the conditions that might determine the number of aggregates in the blood, and whether they are affected by the drug hydroxurea, which is commonly used to treat sickle cell disease.

In addition to Brittain, other authors of the study are: Leslie V. Parise, Ph.D., department chair and professor of biochemistry and biophysics; Dr. Kenneth I. Ataga, assistant professor of medicine; Dr. Eugene P. Orringer, professor of medicine; and Dr. Christine M. Knoll, a fellow in pediatric hematology and oncology.

Support for the research came from National Heart, Lung, and Blood Institute, a component of the National Institutes of Health and the General Clinical Research Center at UNC.

The study can be found at: http://www.blackwell-synergy.com

Note:Brittain can be reached at (919) 962-1058 or julia_brittain@med.unc.edu and Parise can be reached at (919) 966-2238 or parise@med.unc.edu.

School of Medicine contact: Leslie Lang, (919) 843-9687, llang@med.unc.edu

News Services contact: Patric Lane, (919) 962-8596, patric_lane@unc.edu

Recent Research Provides New Interpretations of the Genetic Code

ahc — 2008-04-17T19:45:28Z

Dr. Charles Carter, Professor of Biochemistry & Biophysics, in the April issue of the Nature journal Heredity, reviews two recent papers that present new insights on the codon table and provide an alternative view on the origins of the genetic code.

Yi Zhang Ranked by Thomson Scientific in Top Ten Authors with High Impact Papers

ahc — 2008-04-04T16:14:21Z

Dr. Zhang is the University of North Carolina at Chapel Hill's first Howard Hughes Medical Institute investigator. We congratulate Dr. Zhang and his lab for their high impact contributions to the field.

To read more about the study, please visit: http://scientific.thomson.com/press/2008/8438330/

For the Paper Trail of Life on Mars or Other Planets, Find Cellulose

ahc — 2008-04-07T19:12:26Z

Cellulose is the tough, resilient substance best-known as the major structural component of plant matter. It is one of the most abundant biological materials on Earth, with plants, algae and bacteria generating an estimated 100 gigatons each year. Prehistoric forms of cellulose were made by cyanobacteria, the blue-green algae and bacteria still found in almost every conceivable habitat on land and in the oceans, which is known to have been present on Earth 2.8 billion years ago.

Jack D. Griffith, Ph.D., Kenan Distinguished Professor of microbiology and immunology at the UNC School of Medicine, found cellulose microfibers in samples he took from pristine ancient salt deposits deep beneath the New Mexico high desert.

“The age of the cellulose microfibers we describe in the study is estimated to be 253 million years old. It makes these the oldest native macromolecules to date to have been directly isolated, visualized and examined biochemically,” said Griffith, who is also a virology professor at the UNC Lineberger Comprehensive Cancer Center.

Until now, the oldest evidence of biological material from fragments of ancient protein – found in Tyrannosaurus Rex dinosaur fossils – was dated at 68 million years.

According to Griffith, the most primitive life forms likely developed means of polymerizing glucose – the energy currency of all known carbon-based life forms – into cellulose as a structural molecule. “Cellulose is like the bacteria’s house, the biofilm surrounding them. Plants adopted cellulose as their structural entity, and insects changed cellulose slightly to make kitin of which their exoskeletons are formed,” he said.

Griffith’s study took him to the U.S. Department of Energy’s Waste Isolation Pilot Plant (WIPP), the world’s first underground repository licensed to safely and permanently dispose of radioactive waste left over from nuclear weapons research and production, which is located near Carlsbad, N.M.

The waste is placed more than 2,000 feet below the surface in rooms excavated from the salt deposits that were laid more than 200 million years ago. The site was chosen to hold the waste because salt is somewhat plastic and will flow to seal any cracks that develop.

The salt samples Griffith retrieved from the WIPP were studied in his transmission electron microscopy lab at the Lineberger Comprehensive Cancer Center. In examining the content of fluid “inclusions”, or microscopic bubbles, in the salt and in solid halite (“rock salt”) crystals, he and his team found abundant cellulose microfibers that were “remarkably intact.”

Their examination clearly revealed the cellulose was in the form of microfibers as small as five nanometers in diameter, as well as composite ropes and mats. “The cellulose we isolated from the ancient salt deposits is very much like real, modern day cellulose: it looks like cellulose, behaves like cellulose, it’s chopped up by the same enzymes that cut modern day cellulose and it’s very intact,” Griffith said.

As to evidence of ancient DNA, Griffith said it was observed, but in much lesser amounts than cellulose.

“So in looking for evidence of life on Mars, for bacteria or higher plants that existed on Mars or other planets in the solar system, then looking for cellulose in salt deposits is probably a very good way to go. Cellulose appears to be highly stable and more resistant to ionizing radiation than DNA. And if it is relatively resistant to harsh conditions such as those found in space, it may provide the ideal ‘paper trail’ in the search for life on other planets.”

Co-authors along with Griffith include Smaranda Willcox, research analyst, Lineberger Comprehensive Cancer Center; Dennis W. Powers, Ph.D., geology and geological engineering department, University of Mississippi; Roger Nelson, U.S. Department of Energy, Carlsbad, N.M.; and Bonnie Baxter, Ph.D., biology department, Westminster College, Salt Lake City, Utah.

The study was supported in part by grants from the National Institute of Environmental Health Sciences and the National Institute of General Medical Sciences.

Note: Griffith can be reached at (919) 966-8563, (919) 966-2151 or jdg@med.unc.edu.

School of Medicine contact: Les Lang (919) 843-9687, llang@med.unc.edu
Lineberger Comprehensive Cancer Center contact: Dianne Shaw, (919) 966-7834, dgs@med.unc.edu
News Services contact: Patric Lane, (919) 962-8596, patric_lane@unc.edu

Arrel Toews is an Invited Lecturer for USMLE Review

ahc — 2008-04-01T14:38:15Z

Dr. Toews was selected for his "...excellent teaching..." according to the second year medical students at UNC-Chapel-Hill. The US Medical Licensing exams (USMLE) assess a physician'a ability to apply the knowledge and concepts he or she has learned and to demostrates their skills in patient-care. Step I is the first of the three exams and Dr. Toews will provide his review of Biochemistry on Friday, April 4th to prepare the second years for their upcoming exam. Dr. Toews has a track record of achievements in teaching - just last year he was selected as an Associate Fellow to the UNC Academy of Educators and this year he is a finalist for UNC's Class of 2008 Faculty Award.

Thomas Mullen receives 2008 Dean's Distinguished Dissertation Award

ahc — 2008-04-02T17:09:53Z

Tom is a graduate of Northeastern University where he received his B.S. in Biology and of the University of Connecticut where he received is M.S. in Pathobiology. He joined our department as a doctoral student in Fall of 2003 and is currently a member of Dr. William Marzluff's lab.

Tom's is being honored for his dissertation, titled: "Pathway of Histone mRNA Dedgradation: Oligouridylation followed by Bidirectional Decay." As the winner of the highly competitive Dean's Distinguished Dissertation Award, Tom will receive an invitation to the Graduate School's Student Recognition Event which will be held on April 3, 2008. At the event, he will be presented with an honorarium of $1,000 and a recognition plaque. The department is very proud of Tom's well deserved achievement and wish him all the best in his Dissertation Defense, scheduled for 3pm on Monday, March 17, 2008 in 408 Mary Ellen Jones.

Computer Simulations Point to Key Molecular Basis of Cystic Fibrosis

ahc — 2008-04-21T17:29:45Z

The findings, published Feb. 29 in the open-access on-line journal PLoS Computational Biology, add new knowledge to understanding the development of this fatal disease and may also point the way to new corrective treatments.

Cystic fibrosis (CF) is the most common inherited chronic disease affecting the lung and digestive system. In the United States, about 1 in 3,000 children is born with cystic fibrosis. It is caused by a defective gene that produces a misshapen form of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). People with cystic fibrosis do not have enough CFTR for their cells to work normally because their bodies quickly destroy the mutant protein.

About 90 percent of CF cases are due to the deletion of an amino acid building block in CFTR, in a major domain of the protein called NBD1. Earlier experimental studies have shown that the mutant NBD1 without the amino acid Phe508 has an increased tendency to misfold resulting in the premature degradation of CFTR.

Protein folding is the process in which protein molecules assume their intricate three-dimensional shape. In CF, the molecular basis of this increased misfolding tendency has remained elusive, said senior study author Nikolay Dokholyan, Ph.D., assistant professor of biochemistry and biophysics at UNC’s School of Medicine.

“Understanding the molecular etiology of the disease is a key step to developing pharmaceutical strategies to fight this disease,” Dokholyan said.

Using sophisticated computer modeling techniques, the researchers performed extensive simulations of how normal and mutant NBD1 folded. Known as molecular dynamics simulations, these “virtual experiments” allowed researchers to view how atoms and molecules actually move according to known physical laws. When applied to the NBD1 protein, these simulations showed that the disease-causing mutant exhibits a higher misfolding tendency.

More importantly, by comparing the structures of the normal and the mutant NBD1 domains as they fold, the authors were able to determine critical pairs of amino acid residues that must come together for NBD1 to fold correctly. These interactions are modulators of CFTR folding, and hence, they are potential modulators of CF.

“Computer simulations approximate our understanding of natural phenomena. That our simulations correlated with known experimental studies is remarkable,” Dokholyan said. “More importantly, the molecular details of aberrant NBD1 folding provides guidance for the design of small molecule drugs to correct the most prevalent and pathogenic mutation in CFTR.”

The first author of the study is Adrian Serohijos, a graduate student in both the UNC School of Medicine’s molecular and cellular biophysics program, and in the UNC College of Arts and Sciences’ physics and astronomy department. Other co-authors include John Riordan, Ph.D., co-discoverer of the CFTR gene and professor of biochemistry and biophysics in the UNC School of Medicine; and postdoctoral research associate Tamas Hegedus, Ph.D., of the UNC Cystic Fibrosis Research Center.

The study was supported in part by grants from the Cystic Fibrosis Foundation, the National Institutes of Health, and the American Heart Association.

Note: Dokholyan can be reached at (919) 843-2513 or dokh@med.unc.edu.
The paper can be found at: http://www.ploscompbiol.org/doi/pcbi.1000008.

School of Medicine contact: Stephanie Crayton, (919) 966-2860, scrayton@med.unc.edu
News Services contact: Patric Lane, (919) 962-8596, patric_lane@unc.edu

Discovery of "Overdrive" Protein Could Broaden Drug Design Options

ahc — 2008-04-17T19:42:23Z

The findings have potential implications for drug development as they involve G protein-coupled receptors (GPCRs). These molecules are the target of forty to fifty percent of modern medicinal drugs, such as antihistamines and drugs for high blood pressure.

The study identified the first protein to activate the G-protein signaling pathway from within a cell. In humans, reactions to everything from taste and smell to stimulants like adrenaline or caffeine requires G-protein signaling.

More than half of all drugs, from asthma and heart medicine to antidepressants, target G-protein receptors. Discovering a protein that activates G-proteins from inside a cell could open up an entirely new pathway for drug development, said Henrik Dohlman, Ph.D., senior study author and a professor of biochemistry and biophysics in UNC’s School of Medicine.

“No drug is 100 percent effective, 100 percent free of side effects and 100 percent safe. The more options we have biochemically, the more selective we can be in designing new drugs. If we can find another way of modulating G-proteins, we could expand the drug targets that are available to pharmacology,” Dohlman said.

The study appeared online Feb.7, 2008, in the journal Current Biology and will be published in the Feb. 14, 2008, print edition. Funding was provided by the National Institutes of Health and a UNC Cell and Molecular Biology Program predoctoral fellowship.

Despite 20 years of study, G-protein signaling continues to produce surprises. The advent of the human genome project revealed that some three percent of our DNA is dedicated to these messenger molecules. However, the genomic data also drew biologists away from the research technique the UNC team used to discover the new protein, Dohlman said. “People stopped looking for things that could activate G-proteins using functional criteria,” he said. Instead, they searched for new receptors and activators based on common genetic patterns.

Mike Lee, a graduate student in the UNC School of Medicine’s department of pharmacology, identified the new protein, called Arr4, in yeast cells. Lee employed a mutant form of G-protein to search for any messengers inside the yeast cell with an affinity for G-proteins.

“We went looking for things that could activate G-proteins but don’t resemble known receptors,” Lee said.

He identified seven proteins that weren’t receptors, but did bind to G-proteins, and did further tests on one of the seven proteins, Arr4, to determine its function.

In yeast, Arr4 is involved in cell fusion, a process in which two yeasts fuse together to form one cell, combining their genetic data. A G-protein coupled receptor (GPCR) controls cell fusion, while Arr4 appears to play a supporting role.

Lee said he thinks that Arr4 may allow the cell to go through several additional rounds of signal activation without needing to go back to the receptor.

“Our current thinking is it’s not so much that this is the ignition for signaling, it’s more like an overdrive. Once the pathway is activated by the hormone outside, Arr4 sustains the activity inside,” Lee said. “What we don’t know is if Arr4 is itself stimulated by some signal, and of course we’re very interested in finding out if that’s the case.”

Note: Dohlman can be reached at (919) 843-6894 or hdohlman@med.unc.edu
School of Medicine contact: Les Lang, (919) 843-9687 or llang@med.unc.edu
News Services contact: Patric Lane , (919) 962-8596 or patric_lane@unc.edu

Beverly Errede Elected as an Associate Fellow to the UNC Academy of Educators

ahc — 2008-03-06T21:44:13Z

Dr. Errede joined the Department of Biochemistry & Biophysics in 1995. Her research interest focuses on the Function and Regulation of MAP-kinase Activation Pathways in Saccaromyces Cerevisiae. According to the Academy guidelines, as an Associate Fellow, Dr. Errede will promote and support excellence in teaching and the work and career paths of excellent teachers; promote and fund curricular innovation, evidence-based curricular change and a scholarly approach to the education mission; provide a forum for education leadership and advice for the Dean, Vice Dean, Executive Associate Dean for Medical Education and the leadership of the curriculum; and serve as a mentor for younger teaching faculty.

Protein controls blood vessel formation, offers new drug target

ahc — 2008-04-01T20:26:41Z

A protein called CIB1, discovered by researchers at the University of North Carolina at Chapel Hill School of Medicine, appears to play a major role in controlling new blood vessel growth, offering a target for drug treatments to help the body repair itself after injury and control unwanted blood vessel growth.

“In the future, this knowledge may help our ability to control blood vessel growth in disease situations such as wound healing, retinal diseases and diabetes,” said Leslie Parise, Ph.D., senior study author and professor and chair of biochemistry and biophysics in UNC’s School of Medicine.

The results will appear in an upcoming print issue of the journal Circulation Research and were published online Dec. 1, 2007. The research was funded by the National Institutes of Health.

Parise’s lab first discovered the protein in 1997. It was originally found in blood platelets. CIB1 keeps blood platelets from sticking together, acting as a natural anti-coagulant to prevent clots that might lead to heart attacks or strokes. But further research showed the protein appears in almost every cell type in the body, Parise said. For example, male mice bred without both copies of the CIB1 gene are infertile.

In the current study, Parise and her colleagues found CIB1 in the endothelial cells that line all blood vessels. These cells jump-start new blood vessel growth by a process called angiogenesis. During angiogenesis, biological signals prompt endothelial cells to release enzymes and other chemicals that allow them to move away from existing blood vessels and form new ones.

While angiogenesis plays a critical role in embryo growth, CIB1 appears to only affect blood vessel growth after injury, sometimes called pathological or adaptive angiogenesis. Mice born without copies of the CIB1 gene survive and are reasonably healthy unless injured, Parise said.

“CIB1 appears to be an attractive drug target to control blood vessel growth since it does not play an essential role during fetal development but instead plays an important role in pathological forms of blood vessel growth,” said first author and UNC medical student Mohamed Zayed, Ph.D.

In experiments in mice missing CIB1 genes, the researchers found that the protein is critical for angiogenesis in the retina and in hind legs. In both cases, the new blood vessel growth was prompted by ischemia, or restricted blood flow. However, clinicians treating retinal disease need to restrict blood vessel growth in the eyes, while patients with restricted blood flow in their limbs need to grow blood vessels. Therefore, CIB1 could be a target for both pro- and anti-angiogenic drug therapies.

Parise notes that the lab is still determining the exact role CIB1 plays in angiogenesis. “We think it’s involved in the chemical pathways that control blood vessel growth, such as signal transduction events,” she said. It is also likely that CIB1 is one of many genes that contribute to angiogenesis during ischemia, inflammation and perhaps even tumor growth.

Study co-authors with Parise and Zayad include Weiping Yuan, Tina M. Leisner, Dan Chalothorn, Andrew W. McFadden, Michael D. Schaller, M. Elizabeth Hartnett and James E. Faber, all of UNC.

Note: Please visit the Parise lab for more information.

School of Medicine contact: Les Lang, (919) 843-9687
News Services contact: Clinton Colmenares, (919) 843-1991

Leslie Parise Elected as an AAAS Fellow

ahc — 2008-04-07T18:57:55Z

Election as a Fellow of the American Association for the Advancement of Science (AAAS), the world’s largest general scientific society, is an honor bestowed upon members by their peers. Fellows are recognized for meritorious efforts to advance science or its applications. Dr. Parise has been awarded this distinction for her contributions in the field of biological sciences. At the 2007 AAAS Fellows induction ceremony on February 16, 2008, held in Boston, Massachusetts, Dr. Parise was presented with her Fellowship Rosette and Fellowship certificate by AAAS President, David Baltimore.

Henrik Dohlman Selected as Member for NIH Study Section

ahc — 2008-04-01T14:51:55Z

Members are selected on the basis of their demonstrated competence and achievement in their scientific disciplines as evidenced by the quality of research accomplishments, publications in scientific journals, and other significant scientific activities, achievements and honors. Service on a study section also requires mature judgement and objectivity as well as the ability to work effectively in a group, qualities that Dr. Dohlman will bring to this important task. Study sections review grant applications submitted to the NIH, ake recommendations on these applications to the appropriate NIH national advisory council or board, and survey the status of research in their fields of science. These functions are of great value to medical and allied research in this country.