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CHEMISTRY

Rebecca Alexander

  • CAREER: Dissecting Domain/Domain Communication in Methionyl-tRNA Synthetase
    Awarded: $121,619 for the period 6/1/07 to 5/31/08
    Source: National Science Foundation (NSF)

    The project’s ultimate goal is to characterize long-range domain/domain communication in Escherichia coli methionyl-tRNA synthetase (MetRS), for which tRNA anticodon binding is a strong aminoacylation determinant. Objectives are based on the hypothesis that efficient catalysis by MetRS requires conformational rearrangements of both tRNA and MetRS that are induced by cognate tRNA anticodon binding. Mutagenesis, kinetics, and spectroscopic approaches are used to investigate how a specific peptide component at the domain interface of MetRS contributes to interdomain communication. In addition, crystallography of MetRs in complex with its natural tRNA substrate and a nonhydrolyzable aminoacyl adenylate analog is being pursued to observe structural differences in the complex relative to unliganded enzyme.

  • Dissecting Protein and Nucleic Acid Contributions to Efficient tRNA Aminoacylation
    Awarded $50,000 for the period 10/1/06 to 9/30/07
    Source: National Foundation for Cancer Research

These studies will guide synthesis of small molecules as drugs that inhibit processes involved in cancer and other human diseases and investigate the correlation between accuracy control pathways and subsequent disease states, such as inflammation and cancer. In particular, links between homocysteine, cardiovascular disease, and colorectal cancer will be studied in mammalian cells.

  • Support for Research Technician for Collaborative Projects
    Awarded $36,000 for the period 5/2/05 to 5/1/06
    Source: Scripps Research Institute

    The Scripps Research Institute has offered to pay the salary of a research technician to facilitate three collaborative projects with Dr. Alexander’s laboratory. These structural and mechanistic studies of methionyl-tRNA synthetase (MetRS) extend and enrich Dr. Alexander’s current effort, supported by the National Foundation for Cancer Research.

  • Biochemistry through Biotechnology: Undergraduate Laboratory Enhancement
    Awarded $18,000 for the period 8/1/05 to 7/31/06
    Source: North Carolina Biotechnology Center (NCBC)

    Funds will be used to purchase equipment and supplies to enhance the biotechnology training of WFU undergraduates. A new, one-semester biochemistry laboratory course taken at the junior or senior level, in association with the two-semester biochemistry lecture series developed jointly by the Chemistry and Biology departments, consists of an 11-week study of the enzyme lactate dehydrogenase (LDH), which students will isolate from beef heart, purify by chromatography, and quantify and assay using spectrophotometric methods. Molecular biology approaches, such as PCR of the LDH gene and transgenic expression, will also be taught. With the faculty now in place to expand the undergraduate curriculum to include biochemistry courses and a new local and regional emphasis on expanding biotechnology, WFU is poised to provide undergraduates the background to enter this growing employment market or to receive further academic training.

  • Structural and Mechanistic Studies of Methionyl-tRNA Synthetase
    Awarded $25,000 for the period 4/1/05 to 10/31/05
    Source: National Foundation for Cancer Research
Dr. Alexander’s laboratory is pursuing three projects in collaboration with researchers at the Scripps Research Institute. The partners will undertake structural and mechanistic studies of methionyl-tRNA synthetase (MetRS) that will inform the development of cancer therapies.
  • Research Infrastructure in Minority Institutions (RIMI)
    Awarded $7,716 for the period 10/1/06 to 9/29/07
    Source: National Institutes of Health (NIH)
When the temperature drops, bacteria significantly overproduce a protein called CsdA. It may work to unwind RNA, because at low temperatures, an increase in RNA secondary structure would inhibit mRNA translation at the ribosome. In collaboration with PI Pamela Jones, a microbiologist at Winston-Salem State University, Dr. Alexander will purify CsdA mutants and assay their effect on RNA binding and unwinding in vitro.
  • Chemistry-Biology Biomolecular Imaging Center
    Awarded $71,805 for the period 1/1/03 to 12/31/03
    Source: NCBC
The goal is to provide state-of-the-art instrumentation for sensitive detection and quantitation of radiolabeled probes and other biomolecules after analytical separation on 2-dimensional media, such as gels, blots, and chromatography plates. The instrument will facilitate the research efforts of both the Biology and Chemistry departments, which are committed to biotechnology-related, interdisciplinary research and training students to enter biomedical and biotechnology careers. The seven faculty investigators who collaborated on the proposal will benefit from the technology's impact on their programs in DNA/drug interactions, protein synthesis, protein/RNA interactions, and the expression of plant and animal genes.
  • Tethered Diffusion of an Enzyme Substrate
    Awarded $7,200 for the period 1/03-1/04
    Source: WFU Science Research Fund
Substrate binding by enzymes is typically a bimolecular process, often viewed as a random, diffusion-controlled collision between two molecules. Some enzyme/substrate interactions, however, approach or even exceed diffusion-controlled limits (~109 M-1sec-1). For example, enzymes have been observed to electrostatically "steer" a substrate toward the active site for catalysis. This project investigates methionyl-tRNA synthetase as a model system for substrate movement across an enzyme surface. The distance, rate, and path of methionyl adenylate diffusion from the enzyme active site to remote lysine residues will be determined through mass spectrometry of methionylated protein in conjunction with gel electrophoresis, mutagenesis, and kinetic assays.
  • Mirror-Image Inhibitors of an Essential Bacterial Protein
    Awarded $55,000 for the period 9/1/01 to 2/28/03
    Source: NCBC

Bacterial initiation factor 1 (IF1) is a small protein required for bacterial growth. Although its precise function is poorly understood, structural studies suggest that it binds to the RNA portion of the small ribosomal subunit involved in decoding and accuracy control. The project first aims to characterize IF1's RNA-binding properties. The long-range goal is to identify nuclease-resistant inhibitors of IF1 for use as drugs and diagnostic probes. The design of such inhibitors will be based on a mirror-image approach that has proved successful for small molecules and peptides but never before been applied to a nucleic acid binding protein. A combinatorial RNA library will be introduced to immobilized D-IF1, the chiral inversion of the naturally occurring IF1. Molecules that bind with high affinity will then be synthesized with the native orientation as potential inhibitors of (L-) IF1.These mirror-image inhibitors are insensitive to the cellular nucleases that rapidly degrade most nucleic acid aptamers, making them good candidates for antibacterial drugs.

Ulrich Bierbach

  • Novel DNA-Metalating Hybrid Anticancer Agents
    Awarded $222,078 for the period 5/1/06 to 4/30/07, Year 4 of 5
    Source: NIH

    Dr. Bierbach's recent discovery of a conjugate that exhibits unusual biological and chemical properties has sparked a research program at the interface of biocoordination chemistry, molecular/structural biology, and anticancer drug development. Cancer chemotherapy would be vastly improved if it could contend with the pernicious variety of tumors and types of resistance. To identify a prototypical conjugate that might have this capacity, the project will synthesize a library of structural derivatives and test them in a broad range of cell lines (leukemia, brain, colon, ovary, lung, and breast).

    The goal is a fundamental understanding of small molecule/DNA interactions and their consequences for nucleic acid structure and recognition. Specifically, it will demonstrate that divalent platinum can by hijacked from its natural target, guanine-N7, if the metal's covalent binding is dominated by the tethered intercalating unit rather than simple electrostatics. The results should reveal novel concepts of interest to drug discovery and bioinorganic chemistry.

  • Design of Novel Zinc-Chelating Agents as Inhibitors of Matrix Metalloproteinases (MMPs) for the Management of Pathological Conditions
    Awarded $8,495 for the period 1/1/03 to 1/1/04
    Source: WFU Science Research Fund
Matrix metalloproteinase (MMP), a zinc-dependent endopeptidase, plays a primary role in cancer metastasis and other pathological conditions. This research aims to develop a new type of MMP inhibitor that, unlike treatments currently under clinical evaluation, irreversibly removes the divalent metal from the active site of the enzyme. The compounds of interest are novel tetradentate N-salicylidene-L-(homo)cysteinato chelating agents. Two new chelators will be synthesized and fully characterized, and their metal-binding properties studied using various techniques, including X-ray crystallography, NMR spectroscopy, combined liquid chromatography/ mass spectrometry, and potentiometric titrations. Enzyme assays will be used to establish their inhibitory properties.
  • Photochemistry and Photobiology of Novel DNA-Targeted Light-Activatable Rhodium (III) Ammine Compounds
    Awarded $55,000 for the period 9/1/01 to 2/28/03
    Source: NCBC

Photochemotherapy is a new treatment modality for certain superficial cancers, such as skin cancer. This project will design a drug derived from the metal rhodium. Rhodium is chemically inert but undergoes rapid reactions when irradiated. The metal will be linked to an organic carrier system with a high affinity for DNA. The biological activity of these agents will be assessed in an in vitro model using leukemia cells to gain insight into their mechanism. 

Christa Colyer

  • Noncovalent labeling and CE-LIF strategies for the determination of intact microorganisms
    Awarded $75,000 for the period 8/1/07 to 1/31/09
    Source: North Carolina Biotechnology Center

Analytical tools that can be adapted to a wide range of analyte types are invaluable in interdisciplinary science. They must deliver measurements with high efficiency and high sensitivity, especially for targets within complex matrices. Two strategies involve noncovalent interactions between protein-based analytes and new fluorescent probes that use capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). First, however, their governing physicochemical parameters must be characterized and then important, innovative applications explored. The project aims to devise tools and methodologies for supramolecular entities, such as intact microbes.

It will address three areas:

  1. the need for more sensitive microbe detection by (a) transposing our noncovalent labeling methods for free solution to the more challenging applied problem of surface-binding proteins of intact microbes, such as bacterial spores; (b) ascertaining fluorescence and absorption changes in selected probes upon complexation with microbes of interest; and (c) determining saturable binding curves that can be used to quantitate microbes;
  2. the need for a quantitative understanding how fluorescent probes interact with microbe surface proteins, recognizing that dye/microorganism interactions might compete with microorganism interactions with buffer modifiers used to improve separation efficiencies, by completing various blinding studies, including CE-Frontal Analysis. CE-Hummel Dreyer, and NECEEM (nonequilibrium capillary electrophoresis of equilibrium mixtures); and
  3. the need for greater differentiation among various-sized microorganisms, despite their remarkably similar mobilities by applying optimal noncovalent labeling strategies identified in goals 1 and 2 to individual microbes and mixtures and optimizing CE-LIF separation methodology.

Successful completion of these studies should facilitate development of reagent kits and mobile, point-of-contact CE-LIF instruments capable of simple, inexpensive, and rapid fingerprinting of a variety of microorganisms with applications in the fields of forensics, homeland security, clinical screening, and environmental protection.            

  • Collaborative Exploration: Using CE to Quantify PE Pigment Concentrations
    Awarded $5,000 for the period 8/1/06 to 7/1/07
    Source: NASA

This project aims to demonstrate the utility of capillary electrophoresis with laser-induced fluorescence detection for analyzing more phycobiliproteins than those previously extracted from a single synechococcus culture. By applying the group’s extraction and analysis protocols to 15 different samples, including other synechococcus cultures, a cryptomonad culture, and a rhodamonas culture, the project will evaluate the comparative effectiveness of this methodology and begin the process of modification. 

  • Real-time Bioaerosol Sensor with Airborne Taggant Applicator
    Awarded $80,000 for the period 8/25/05 to 8/24/06
    Source: Department of Homeland Security

The project will develop a low-cost, real-time, optical bioaerosol sensor that can discriminate many types of naturally occurring biological aerosols from biological aerosol threats and improve the lower detection limit for singlet spores through the airborne application of two optical taggants. Airborne particles are illuminated one at a time in two separate but correlated regions that allow five measurements.

The resulting sensor will significantly enhance an existing bioaerosol trigger. It is expected to deliver a response in less than one minute with a false-alarm rate of less than once per year with a 98% confidence level at an agent concentration of 1000 CFU/liter of air. The system is expected to detect all classes of agent: spore, cellular, viral, and protein toxin. The sensor is also expected to come close to the desired cost characteristics with low annual maintenance costs.

Bradley T. Jones

  • ARI-SA, a Portable Tungsten Coil Atomic Emission Detector for Nuclear Forensics
    Awarded $100,469 for the period 9/1/07 to 8/31/08
    Source: National Science Foundation

This project addresses a unique aspect of nuclear threat detection. Terrorists are less likely to use enriched isotopes capable of sustaining nuclear chain reactions than the thousands of radioactive sources stemming from industrial radiography, radiotherapy, irradiators, and thermo-electric generators, which could be released into public water and food supplies or via a Radioactive Dispersion Device (dirty bomb). The project’s main goal is to develop the first handheld atomic emission spectrometer capable of simultaneous multi-element analysis at the part-per-billion level. Samples deposited on a tungsten coil, extracted from a light bulb and powered by a car battery, will emit characteristic spectra. It will enable field scientists to perform nuclear forensic analyses on the spot, without the need for sample collection and shipment to contract labs. Decisions will occur in real-time. The field analyst can follow the concentration gradient upstream to the source of contamination or detonation, and the radioactive material’s metal fingerprint may offer insight into its procurement. While many systems for detecting radioactive material prior to release are in development, the proposed device will be applied in those hopefully few but critical cases where release occurs - at the moment of greatest public concern or even panic.

The project will engage PhD students from Wake Forest University, MS students from Western Carolina University, underrepresented minority undergraduate researchers from Winthrop University, and a world-renowned expert from the Federal University of Sao Carlos, Brazil. The spectrometer will be marketed by a capable and successful instrument manufacturer, Teledyne Leeman Labs (NH).

  • with Thomas A. Arcury, Family and Community Medicine
    Cadmium, Lead, and Arsenic Exposure among North Carolina Farmworkers
    Awarded $20,000; $10,000 Reynolda campus, $10,000 Health Sciences
    Source: WFU Cross-Campus Collaborative Research Support Fund

    The project seeks to identify the risks in working at farm sites previously treated with toxic metal-containing pesticides and fertilizers. While organic pesticides are known risks to migrant workers, the risks from exposure to metal-containing agricultural products are not well understood. Farmworkers will be recruited, complete questionnaires, and provide urine samples. The project will develop a method to determine cadmium, lead, and arsenic levels in urine and, once perfected, used to analyze 260 samples. The toxic metal body burden will be compared with other potential risk factors associated with farmworker lifestyle, and the results disseminated to the at-risk population.

  • A Small Portable Tungsten Coil Spectrometer
    Awarded $5,000 for the period 11/18/05 to 11/17/06
    Source: WFU Science Research Fund

    A low-cost, portable atomic spectrometer will be designed and evaluated for use in field applications, such as environmental monitoring and drinking water testing. It will use a tungsten coil as an atomization device and to generate continuum radiation. The instrument will measure either atomic absorption or atomic emission spectra, depending on the optical alignment. The atomizer will be coupled to a small, hand-held, high-resolution detection system using a fiber-optic cable. The system will be the simplest and most portable multi-element atomic spectrometer ever described.

  • Faculty Recruitment Grant: Assistant Professor of Chemistry
    Awarded: $100,000 for the period 6/1/05 to 5/31/06
    Source: NCBC

Funds will assist in recruiting a third Assistant Professor of Biochemistry (1) to complete the biochemistry division on the Reynolda Campus; (2) to encourage recruitment of undergraduate and graduate students in the program; and (3) to enhance biological expertise in western North Carolina. The successful candidate will help to develop the curricula in biological chemistry and teach courses leading to the BS and BA degrees in chemistry with a concentration in biochemistry. The candidate will also establish a research program that complements current faculty efforts. The purchase of major equipment and supplies will support the university's bioscience infrastructure as a whole, and Wake Forest will match grant funds with start-up funding and by renovating biochemistry research space.

  • with Abdessadek Lachgar
    Upgrade of a Single Crystal Diffractometer
    Awarded $117,500 for the period 1/1/03 to 1/1/04
    Source: NSF
X-ray crystallography has become an essential analytical method for the success of Wake Forest chemistry research, which has increased from 33 publications in 1995 to 93 in 2001. Funds will support the purchase of a new serial detector for an X-ray system originally purchased with NSF funding in 1996. Detection capability has had a tremendous positive impact on crystal structure analysis due to 1) faster data collection; 2) ability to collect data from large sections of the entire reciprocal space, in contrast with serial detectors that explore only the areas where reflections are expected; and 3) increased sensitivity that allows data collection on very small or weakly diffracting crystals. The 4-circle goniometer adds a powerful tool for investigating twinning and superstructure problems.

Paul Jones

  • Oxidative Radical Cyclizations: Mechanistic and Synthetic Investigations
    Awarded $233,700 for the period 9/1/05 to 8/31/08
    Source: NSF

    Dr. Jones’s laboratory has discovered a new photochemical reaction of anthraquinoes. It consists of two unprecedented chemical steps: the cyclization of a phenol radical on a tethered alkene and electron transfer from a carbocation to a semiquionone radical. The project will first establish the reaction’s scope and synthetic utility, with the hope of using it to prepare biologically active anthraquinones. Next, it will try to extending the reaction’s scope beyond anthraquinones to any phenol with an alkene tethered to the ortho position. Results could have repercussions for physical organic as well as synthetic organic chemistry.

  • Ionic Lubricants Incorporating Nanomaterials
    Awarded: $31,000 for the period 9/30/04 to 6/29/05
    Source: Air Force Office of Scientific Research (AFOSR)

    The project teams Dr. Jones’s lab with NanoTechLabs to synthesize and to evaluate ionic liquid/carbon nanotube-based lubricants to reduce bearing and other mechanical wear. They aim, first, to use unique cations, based on chiral imidazoliums developed at Wake Forest, as a basis for the lubricant. The presence of chiral centers in the alkyl substituents in combination with chiral anions in a salt depresses its melting point and prevents crystallization. Commercially available anions will be combined with the new cations to form the lubricant. Second, they will incorporate single-walled carbon nanotubes (SWNTs) into the ionic lubricants to reduce friction and to enhance thermal stability. Carbon nanotubes should affect the molecular ordering of the lubricant and change with the lengths of the nanotubes.

Mechanical properties will be evaluated by pin-on-disk tribometer. Nanoscale wear analysis (nanotribology) using atomic force microscopy (AFM) will evaluate lubricant film thickness and morphology as well as any boundary layer formed by lubricant decomposition. AFM will allow film properties to be measured through a range of temperatures by use of hot and cold stages. Scanning electron microscopy (SEM) will permit microstructural analysis of the wear surface, and nanotube length and dispersion will be characterized by transmission electron microscopy (TEM).

Currently, lubrication in space mechanisms, electronics, and the computer industry concentrates on perfluoropolyethers (PFPEs), which, however, have poor solubility and are susceptible to autocatalytic degradation. Ionic liquids have a number of desirable characteristics, including negligible volatility, nonflammability, high thermal stability, low melting point, and broad liquid range. Versatile lubricants of use on a variety of materials, such as ceramics, aluminum, and steel, will be of great value to the Air Force and industry. Because of their controlled miscibility with organic compounds and low volatility, ionic liquids may also play an important role in green synthesis.

  • New Photochemistry for Visible Light-Initiated Photoactivation of Enzymes and Biocides
    Awarded $215,530 for the period 4/1/04 to 3/31/07
    Source: NIH

Photodynamic Therapy (PDT) treats diseases with light-activated chemotherapeutics and most often involves the formation of singlet oxygen via energy transfer from dye sensitizers. Singlet oxygen is highly reactive and relatively unselective, and the sensitizer can make the patient sensitive to bright light for weeks.

The long-term goal of this project is to develop a new PDT system that does not use singlet oxygen or leave the patient sensitive to light. Its achievement will require a new chemistry and biochemistry for the photochemical production of biologically active molecules.

Specific aims are:
1) To develop a system that can act as a photolabile, amine-protecting group using visible light;
2) To photoactivate enzymes in vitro;
3) To develop photochemistry capable of photoreleasing biologically active aldehydes; and
4) To demonstrate in vitro biological activity that depends on visible light.

These aims are based on the hypothesis that photoactive agents with more selective biological activity will prove more predictable and allow the tailoring of PDT agents to specific diseases. For example, a photoactivated clot-busting enzyme could form the basis of an effective treatment for Central Retinal Vein Occlusion, which currently has no treatment, while a photoactivated antiviral agent could treat a number of dermal viral infections. An effective general photoactivation scheme for biomolecules could have limitless therapeutic applications.
  • Photoinduced Electron Transfer and Photoreduction in Room Temperature Ionic Liquids
    Awarded $35,000 for the period 9/01/02 to 8/1/04
    Source: ACS
Dr. Jones seeks to combine the environmentally friendly qualities of photochemistry with the recyclable qualities of ionic liquids to develop synthetic procedures that generate little organic chemical waste.
  • New Strategies for Photodynamic Therapy
    Awarded $55,000 for the period 9/1/01 to 2/28/03
    Source: NCBC

    The project aims to develop a method to activate enzymes using visible light. Two enzymes, TPA and thrombin, are potential agents for the treatment of two devastating diseases responsible for much of the world's blindness. However, neither enzyme can be used directly due to the risk of inducing stroke. By using an enzyme blocked with a photoreversible inhibitor, selective irradiation of the diseased site would avoid this side effect, but introduce ultraviolet light, which is also prohibitively harmful. Dr. Jones will develop technology that uses visible light, bringing us closer to a treatment for these ocular disorders.

Angela Glisan King

  • Rural Exposure to Biotechnology
    Awarded $4,925 for the period 5/15/04 to 7/1/05
    Source: NCBC


    This partnership between Wake Forest University and South Stokes High School aims to prepare and to encourage a greater number of high school students from the rural target audience to pursue interests and careers in biotechnology at any level. This objective will be achieved by providing:
    • electrophoresis and enzyme kinetics equipment and lab supplies not used in standard high school experiments and thus not provided by the school budget at a rural North Carolina high school;
    • training for all the school's science teachers on how to use the equipment and ideas for incorporating biotechnology into the Standard Course of Study; and
    • a field trip for the rural students to a biotechnology laboratory to broaden their career horizons.

  • The Science Behind Biotechnology: A Workshop for High School Teachers
    Awarded $14,700 for the period 2/1/03 to 5/1/04
    Source: NCBC
The NSF-funded "Science Behind Biotechnology" workshop will be held in summer 2003 for 2 weeks with a target audience of 24 biology and chemistry teachers from 8 local high schools. Participants will learn about biotechnology; conduct laboratory investigations suitable for classroom adoption; explore computer and internet resources related to biotechnology; take field trips to working biotechnology laboratories; and meet researchers. Activities are designed to expose teachers to a multitude of biotechnology techniques using the same piece of equipment: an affordable and durable Spec 20 spectrometer, for which funds were requested from NC Biotech.
  • SCIMAX
    Awarded $82,263 for the period 9/1/05 to 8/31/06
    Source: NSF, Urban Systemic Program in Science, Mathematics, and Technology Education
SCIMAX (SCIENCE AND MATH EXCELLENCE) is a community-driven, K-16 partnership to ensure that all students graduating from Winston-Salem/Forsyth County Schools are able to pursue postsecondary studies and/or careers in science and mathematics.
  • Revitalizing the Chemistry Program's First Two Years
    Awarded $25,000 for the period 1/15/01 to 5/31/02
    Source: Camille and Henry Dreyfus Foundation

    The project will improve the undergraduate chemistry program through a new course sequence that reduces repetition while emphasizing applications and by redesigning laboratories to incorporate molecular modeling and biotechnology tools and modern pedagogical approaches, such as project-based and inquiry-based experiments.

S. Bruce King

  • with Daniel Kim-Shapiro, Physics
    Nitric Oxide Donor Compounds for the Treatment of Hemolytic Conditions
    Awarded $161,560 for the period 1/8/08 to 12/31/08
    Source: National Institutes of Health

Nitric Oxide (NO) is synthesized in the endothelial cells surrounding blood vessels and signals smooth muscles to relax and increase blood flow. Hemoglobin (Hb) actively scavenges NO. In normal physiology, its scavenging is reduced due to  its compartmentalization in red blood cells, but in several diseased conditions, including hemolytic anemias, such as sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and cardiopulmonary bypass, Hb is released into the plasma compartment and can efficiently scavenge NO. This increased NO scavenging leads to a host of complications contributing to morbidity and mortality.

Administering NO through inhalation restores normal NO responsiveness and shows promise as a treatment, but it is not practical for chronic treatment. This project tests and, to some extent, synthesizes compounds that may eventually be taken intravenously or orally. Unlike many therapeutic compounds, they will be cell-impermeable, acting in the plasma compartment to react preferentially with cell-free Hb and inactivate its NO scavenging ability. Lead compounds include NONOates (NO donors), nitroxyl donors, and possibly nitrated lipids and nitrites.

  • Nitric Oxide-Producing Reactions of Hydroxyurea
    Awarded $47,058 supplement for the period 12/1/06 to 11/30/07
    Source: National Institutes of Health

Hydroxyurea is a new treatment for sickle cell disease, a painful condition that affects 1 in 600 Americans of African descent. The project's long-term goal is to explain how hydroxyurea's nitric oxide (NO)-producing reactions contribute to sickle cell therapy in order to improve it. Product analysis and kinetic and spectroscopic studies will determine the mechanism of hydroxyurea's NO production in vitro, and similar studies of various tissues and purified enzymes incubated with hydroxyurea will reveal both the mechanism and site of in vivo NO formation. Specifically, these results will distinguish hydrolytic from oxidative mechanisms.

Spectroscopic methods and product analysis will also be used to demonstrate the extent of enzyme activation and the ultimate products and kinetics of the reaction of hydroxyurea-derived NO and the identified target proteins, soluble guanylate cyclase and cell-free hemoglobin. These results will indicate the ability of hydroxyurea or hydroxyurea-derived NO to influence or to react with these target proteins, providing evidence for a mechanism for the beneficial effects of hydroxyurea treatment. Unique hydroxyurea-based NO delivery systems and water-soluable nitroxyl donors will be prepared through chemical synthesis. Their ability to release NO will be determined using spectroscopic and cyclic voltammetric studies, and these results will reveal the ability of these new systems to act as NO or nitroxyl donors.

  • with Charles Morrow, Biochemistry
    • Structural Requirements of Nitrated Fatty Acids: Natural Cellular Signaling Agents and Nitric Oxide Donors
    Awarded $20,000 for the period 5/06-5/07
    Source: WFU Cross-Campus Research Support Fund


    Recently, nitrated fatty acids have been identified as common constituents of various biologically crucial cells. Under physiological conditions, they activate the nuclear transcription factor, peroxisomal proliferator-activated receptor (PPAR), and donate nitric oxide (NO). This project will examine the relationship of their structure, particularly the position of nitration, to these functions. Defined nitrated fatty acids will be prepared by chemical synthesis and evaluated for their ability to bind PPAR and to induce transcription. They will also be evaluated as NO donors by various analytical techniques. Results should clearly define the structural requirements for activating PPAR and NO release and how this pathway is involved in both normal and pathophysiology.

  • with Jacquelyn Fetrow, Computer Science and Physics
    Profiling of Redox-Sensitive Signaling Proteins
    Awarded $32,340 for the period 5/1/06 to 4/30/07, Year 2
    Source: NIH

For over twenty years, redox mechanisms have been implicated in cancer development, but the lack of large-scale methods to identify proteins that respond to cellular redox changes is a serious barrier to progress. This project hypothesizes that redox signaling affects the initiation of cell proliferation and transformation. Because the tools to test it directly are not available, Dr. King and collaborators will integrate analytical protein chemistry, cell biology, and bioinformatics to develop the reagents and methods to identify modifications in proteins involved in signal transduction pathways. The successful development of this technology will allow the underlying hypothesis to be tested in a future broad-scale research project.

  • Cost Extension for NIH Minority Supplement, Nitric Oxide-Producing
    Reactions of Hydroxyurea
    Awarded $30,279 for the period 5/15/04 to 8/15/04
    Source: NIH, supplement

The supplement supports the collaboration of Dr. Mamudu Yakubu, Associate Professor of Chemistry and Physics at Elizabeth City State University.

  • with Leslie Poole, Biochemistry
    Development of Sensitive Chemical Probes to Detect Biologically Significant Changes in the Cysteine Redox State of Target Proteins
    Awarded $15,000 for the period 6/03 to 6/04
    Source: WFU Cross-Campus Research Support Fund

    The changing redox states of protein cysteine groups that affect cell signaling in biologically important target proteins has not been examined. Since gel-compatible techniques for detecting cysteine sulfenic acids do not exist, their biological relevance is severely underappreciated. Reversibly oxidized cysteines can regulate the activity of enzymes and transcriptional regulators and are probably responsible for alterations in cellular redox status that affect cell signaling.

    This project will develop one or more reagents sensitive to cysteine sulfenic acids, using gel and liquid formats to label and detect them in proteins. The long-term goals are to profile cysteine oxidation for given proteins under specific cellular conditions and to elucidate the molecular mechanisms involved in regulating protein functions. By investigating new and under-characterized proteins that, through redox cycling of essential cysteine residues, are involved in responses to inflammatory and proliferative stimuli, for example, new elements of signal transduction pathways may emerge.
  • Synthesis and Evaluation of L-Arginine Derivatives and Mechanistic Probes of Nitric Oxide Synthase
    Awarded $75,000 for the period 1/1/03 to 12/31/04 (Year 3)
    Source: AHA Established Investigator Grant

    The project aims to explain the nitric oxide synthase (NOS)-catalyzed production of nitric oxide (NO) from L-arginine based on three hypotheses: 1) L-arginine acts as an acid catalyst for perferryl-iron-heme-complex formation during the NOS-catalyzed conversion to N-hydroxy-L-arginine; 2) the NOS-catalyzed conversion of N-hydroxy-L-arginine to L-citrulline and NO proceeds through an oxygen-centered, N-hydroxy-L-arginine radical; and 3) this second conversion proceeds through a tetrahedral reaction intermediate.The first hypothesis will be examined by chemical synthesis and evaluation of L-arginine and N-hydroxy-L-arginine derivatives with modified acid-base properties. The second hypothesis will be examined by chemically synthesizing a group of compounds designed to indicate the presence of radical intermediates during the NOS-catalyzed conversion of N-hydroxy-L-arginine to NO. The compounds will be incubated with the enzyme, followed by product analysis, in some cases, by electron paramagnetic resonance spectroscopy. The third hypothesis will be examined by chemical synthesis of a designed, tetrahedral, transition-state analog of the conversion of N-hydroxy-L-arginine to L-citrulline and NO. This compound will be evaluated as a competitive inhibitor of NOS.

  • Reactions of Hydroxyurea with Sickle Cell Hemoglobin
    Awarded $240,837 for the period 9/1/02 to 8/31/03
    Source: NIH

    Hydroxyurea is a new treatment for sickle cell disease, a condition that affects one in six hundred Americans of African descent, yet exactly how it benefits patients remains unknown. The long-term goal of this research is to understand the molecular mechanisms of the reaction between hydroxyurea and sickle cell hemoglobin. The kinetics and product distribution of the reaction of hydroxyurea and oxy, deoxy, and met sickle cell hemoglobin will be determined. The effects of nitric oxide and nitroxyl donors on sickle red blood cells will also be determined, and a new, water-soluble nitroxyl donor developed. Biophysical measurements of the delay time and percent sickle hemoglobin and the rheological properties of purified hemoglobins and red cells will determine the consequences of these reactions. Results should provide information that will inform the design and application of superior treatments.
  • Bio-Organic Chemistry of N-Hydroxyureas and Related Compounds
    Awarded $60,000 for the period 1/00 to 12/05
    Source: Dreyfus Foundation

    The Henry Dreyfus Teacher-Scholar Award supports the teaching and research of outstanding young chemistry faculty. Dr. King's research on the roles of nitric oxide in biological systems, much of it carried out by undergraduates, has implications for new treatments of sickle cell disease and a wide array of other problems.

Abdessadek Lachgar

  • Design and Self-Assembly of Cluster-based Materials
    Awarded $120,000 for the period 1/1/07 to 12/31/07
    Source: NSF

Understanding how to choose and to assemble chemical species into functional materials for photonics and electronics, chemical and biological sensors, energy storage, and catalysis remains a fundamental challenge. Self-assembly is the most promising approach to designing and controlling the bottom-up assembly of molecular objects into well-organized materials with desired physical and chemical properties. Rooted in crystal-engineering principles, the preparation of cluster-based materials brings together two specifically designed building blocks: a cluster and a metal complex with preferred directional bonding requirements that affect framework dimensionality and its properties. Transition metal clusters are of special interest due to their chemical stability, electronic flexibility, and large size compared to mononuclear complexes.

This work will test a novel method of preparing cluster-based materials with specific structure dimensionality and framework topologies. It uses predesigned octahedral clusters and metal complexes as building blocks to achieve the assembly of the hybrid inorganic-organic materials at or near ambient temperatures and allows access to kinetically stable phases. This systematic study will also contribute several novel twists to proven techniques and involve the training of undergraduate and graduate students.

  • Design and Self-Assembly of Cluster-Based Materials
    Awarded a $16,000 supplement for the period 1/1/06 to 12/31/06
    Source: NSF

The funds primarily supported travel and subsistence expenses for African and US-based researchers to attend a one-day workshop at the Third International Conference of the African Materials Research Society. Hosted by the University Hassan II in Marrakech, Morocco, from 7-10 December 2005, the conference encompassed the full spectrum of materials research – from the physics and chemistry of nanomaterials to materials education. It focused on identifying collaborative themes and building partnerships to strengthen the capacity for materials research in Africa. Professor Lachgar was one of the primary organizers and spearheaded the workshop, which consisted of two parts. The first aimed to plan collaborations between Wake Forest University, the University of South Florida, and Kansas State University in the United States and African universities in Morocco, Senegal, and South Africa. The second part, titled “ABCs of Nanotechnology: A Workshop on Atoms, Bits, and Civilization,” focused on the emerging fields of nanoscience and nanotechnology. It was led by George Lisensky from Beloit College and Karen Nordell from Lawrence University, both in Wisconsin.

  • Inter-American Materials Collaboration: Hybrid Inorganic-Organic Materials
    Awarded $33,000 for the period 7/15/05 to 12/31/06
    Source: NSF, CONACYT

    Dr. Lachgar and Dr. Munoz, a colleague at the Autonomous University of Morelos (UAEM), Mexico, will combine their expertise in solid-state materials and metal organic preparation and characterization to develop a collaborative research and educational program. They will investigate novel hybrid inorganic-organic materials involving multifunctional ligands, octahedral and cubic metals, or inorganic clusters. The first year will involve the two PIs, three graduate students, and two undergraduate students, one from each group. The study is expected to provide a framework for the PIs to educate a number of graduate and undergraduate students in the interdisciplinary field of solid-state hybrid inorganic-organic materials, which involves a number of synthesis and characterization methods necessary to any well-trained materials chemist.

  • with Bradley T. Jones
    Upgrade of a Single Crystal Diffractometer
    Awarded $117,500 for the period 1/1/03 to 1/1/04
    Source: NSF

    X-ray crystallography has become an essential analytical method for the success of Wake Forest chemistry research, which has increased from 33 publications in 1995 to 93 in 2001. Funds will support the purchase of a new serial detector for an X-ray system originally purchased with NSF funding in 1996. Detection capability has had a tremendous positive impact on crystal structure analysis due to 1) faster data collection; 2) ability to collect data from large sections of the entire reciprocal space, in contrast with serial detectors that explore only the areas where reflections are expected; and 3) increased sensitivity that allows data collection on very small or weakly diffracting crystals. The 4-circle goniometer adds a powerful tool for investigating twinning and superstructure problems.

  • Preparation and Characterization of Low-Dimensional and Open-Framework Cluster Materials
    Awarded $60,000 for the period 9/1/00 to 8/31/03
    Source: ACS/Petroleum Research Fund (PRF)

The development of low-dimensional inorganic materials constitutes a major area of material sciences. The presence of pores, interlayer or interchain spaces allows for many important technological applications in fields as diverse as nuclear waste management, fuel cells and solid state batteries, and catalysis. The project's objective is to prepare and to investigate the structural and physico-chemical properties of low-dimensional and open-framework materials containing octahedral transition metal clusters, using the "mixed-ligand" approach. A combination of ligands with different charges and sizes is used to affect the cluster framework dimensionality through the formation of cluster units with uneven surface charge distribution, which leads to preferred directions for intercluster linkages. The novel features of the materials show that the oxohalides constitute a new class of materials with structural features that give them a wide range of potential applications. The preliminary investigation has led to remarkable findings that were recently published in some of the best international periodicals in chemical research, including the Journal of the American Chemical Society, Angewandte Chemie, Chemical Communication, and Inorganic Chemistry.

Ronald E. Noftle
Synthesis and Electrochemistry of Thiophene Imides
Awarded $117,000 for the period 7/1/00 to 6/30/03
Source: NIH 

The project's goal is to synthesize and characterize a new series of thiophene imides that can be polymerized to create novel materials with many applications. The polymers' acid-base properties, metal complexing abilities, luminescence, and electrochemical properties will be studied to develop a systematic framework for choosing the R group, which fits a polymer for use as: 1) an ion exchange material for trace metal ion separation; 2) a chromatographic material for the separation of proteins; 3) a complexing agent forming luminescent complexes with rare earth metal ions that can be used as markers; and 4) a trace metal ion sensor. The long-term objective is to design superior separation and detection systems with biomedical applications.

Akbar Salam

  • 21st Century Centre of Excellence Guest Professor
    Awarded JPN YEN 500,000 for the period 12/8/05 to 1/8/06
    Source: Kyoto University, Japan
  • Visiting Fellow, Institute for Theoretical Atomic, Molecular, and Optical Physics (ITAMP)
    Awarded $4,000 for the period 3/19/07 to 4/20/07
    Source: Harvard University, Department of Physics

  • Wiley-International Journal of Quantum Chemistry Young Investigator Award
    $1,000 plus conference registration
    Source: University of Florida’s Quantum Theory Project; the Sanibel Symposium on Atomic, Molecular, Biophysical, and Condensed Matter Theory; and John Wiley & Sons, Inc.

Robert L. Swofford
Technology Challenge Literacy Grant
Awarded $34,328 for the period 9/1/99-8/31/02
Source: Winston-Salem/Forsyth County Schools subcontract

The Winston-Salem/Forsyth County School system has greatly increased graduation requirements for the Class of 2000 and beyond. To help meet the growing needs of students, the district has expanded its teacher training to include Problem-Based Learning as an instructional model. Currently, however, PBL training is paper-based; it could better serve teachers and students if it were delivered on the web. WC/FC schools have partnered with Wake Forest to transfer this content to the web seamlessly.The subcontract adds technology training institutes to the current PBL initiative so that teachers will be better prepared to model its use and deliver its content within the technology-based environment. Trainers and facilitators are available to present over one hundred hours of training under the joint design and administration of WS/FCS and WFU. Teachers will then be able to share their knowledge and abilities with students who must compete in a technological workplace. Participants will have access to hardware and software during the life of the project as well as internet access with the ability to publish and communicate on the web.

Suzanne Tobey

  • Anatioselective Synthesis of apha-Amino phosphonates using an Ene Reaction
    Awarded $50,000 for the period 7/1/07 to 6/30/08
    Source: Herman Frasch Foundation

Synthesis of α-amino phosphonates is fundamentally interesting, technically challenging, and desirable for research-oriented aspects of agrochemical industries, including herbicidal or insecticidal applications, and as tetrahedral surrogates of amino acids for mechanistic studies. This project aims to develop an organic Brønsted acid-promoted Ene reaction, a new synthetic approach that avoids the substrate limitations of existing methods, provides access to new classes of compounds, and circumvents the use and cost of expensive metal catalysts.

  • Synthetic Nicotinic Receptors for Deciphering the Physical Parameters of Nicotine Binding
    Awarded $9,312 for the period 6/06 to 6/07
    Source: WFU Science Research Fund

This research takes a novel approach to elucidating the communication between the two rings of nicotine, as the molecule participates in a recognition event with a synthetic receptor. The goal is to determine the fundamental physical parameters that characterize the molecular recognition event, using electronically modified receptors. A basic understanding of the differential binding of nicotine in different receptor environments will serve as a new design tool for nicotinic analogues, which show potential as therapeutic agents for Alzheimer’s Disease.

Mark Welker

  • New Organosulfur Anticarcinogenic Enzyme Inducers
    Awarded $208,705 for the period 4/1/05 to 3/31/08
    Source: NIH

    The project’s long-term goal is to produce nontoxic cancer chemopreventive agents. A comprehensive cancer treatment strategy will ultimately involve the use of small molecules for both the treatment and prevention of cancer, but to date, much more progress has been made in identifying small molecule antitumor agents than small molecule cancer prevention agents. The proposed work helps to close this gap.

    Chemoprevention of cancer involves the use of chemical agents either to retard or to block carcinogenesis. These agents affect the metabolism of xenobiotic procarcinogens by inducing the enzymes that detoxify potential carcinogens. Typically, phase 1 of xenobiotic metabolism involves oxidative processes, and phase 2, redox or conjugation chemistry. This project will search for chemical agents of low toxicity that elevate phase 2, but not phase 1, enzymes as a cancer prevention strategy.

  • Preparation and Tandem Reactions of Main Group Substituted Dienes
    Awarded: $360,000
    Source: NSF

    The Welker group has shown that certain dienes can be used to reverse the normal endo selectivity of Diels-Alder reactions and provide access to new cycloadduct stereoisomers in high yield and diastereoselectivity. Now, they propose to study tandem reactions of these new compounds. Boron, silicon, and aluminum-substituted dienes offer practical advantages over transition metal-substituted dienes in terms of cost, preparation, and disposal and are more amenable to catalytic chemistry and tandem reactions. This methodology can also access biologically significant core structures that have applications ranging from insect antifeedants to biomedical science.

Their work has been cited several hundred times as of 2004, and other groups have used their previously reported cycloadducts and methodology for making new, functionalized carbocyclic amino acids. Four senior scientists/postdoctoral fellows, 6 graduate students, and 13 undergraduate students have received training in synthetic organic and organometallic chemistry.

  • Catalytic Metal-Mediated Enantioselective Cycloaddition Reactions
    Awarded $254,000 for the period 3/1/01 to 2/28/04
    Source: NSF

    This renewal follows on two prior NSF-supported cycles examining new ways to synthesize molecules with a broad spectrum of biological potential. The Diels-Alder reaction is probably the most important reaction that synthetic chemists use when they want to make six-member rings (hexagons) that contain all carbon atoms. The substituted six-member rings found in nature almost invariably have a specific handedness, or chirality. Molecules with this property cannot be superimposed on their mirror images and are called enantiomers of one another. The challenge is to make only one of the two possible enantiomers. Having demonstrated that both enantio-selective and exo-selective Diels-alder reactions can be done using transition metal-substituted dienes, Dr. Welker’s laboratory will now explore how to best affect reactions that are catalytic rather than stoichiometric in the transition metal complex used. A successful answer will contribute to savings in both material and waste disposal costs.

  • Synthesis of Anti-HIV Agents that Target Retroviral Zinc Fingers
    Awarded $147,320 for the period 3/1/00 to 2/28/03
    Source: NIH

    While treatment of HIV-1 infection with multidrug therapies can delay AIDS, these "cocktails" sometimes fail for a variety of reasons. There is still a great need for new antiviral agents that select for unique targets. Since they are conserved among all known retroviruses, the two retroviral zinc finger motifs of the HIV-1 nucleocapsid p7 (NCp7) protein may prove to be such unique antiviral targets. New sulfur heterocycles that chemically modify the nucleophilic cysteine residues in the NCp7 zinc fingers will be prepared and then screened in collaboration with Dr. William Rice and Achillion Pharmaceuticals. New compound synthesis and active compound binding will be guided by molecular modeling techniques in the laboratory of Dr. David Covell at the NCI-Frederick Center. Dr. Welker will chemically modify the active compounds with the goal of maintaining anti-HIV-1 activity and reducing toxicity. Next, the reaction chemistry of anti-HIV-1 active compounds with glutathione and cysteine will be investigated. Dr. Rice's earlier studies show that glutathione can alter the anti-HIV-1 activity and zinc ejecting ability of these compounds. Their susceptibility to thioloate anion attack could be a preliminary screen that will help to determine activity. Then these compounds could provide models for the chemical modification that is occurring at the cysteine residues in the zinc fingers.
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