SB+B Fellowship Program

Table of Contents

Plan of Study

Facilities

Participating Faculty

About Omaha, NE

Plan of Study

SB+B students are expected to develop a solid foundation in Biochemistry and Molecular Biology (BMB), as well as, develop the technical and theoretical expertise needed to reach a high level of achievement in SB+B. Along with the BMB graduate program, a number of specialized courses and supervised activities are provided to further the intellectual development, and provide teaching experience to our SB+B students

Component	Years	Description/Comment
BMB Core courses	1 & 2	A common core of training in fundamentals of BMB. Grade of B- or better in each course and a GPA of 3.0 are required.
Introduction to SB+B research	1	Students interview with at least 5 faculty members and then select 3 for their 6-8 week introductory research rotations. From these, students will select a laboratory for their dissertation research. Limited to the participating faculty members.
Supervisory committee	1	Immediately after selection of their research advisor, a supervisory committee is formed. The supervisory committee meets with the students biannually to monitor progress in coursework, comprehensive exam and thesis research. They are also examiners for the doctoral thesis defense.
SB+B specialty course	2	BIOC/PHSC 921 Biophysical Chemistry
Ethics course	1 or 2	Students are required to participate once during their graduate career in the UNMC “Responsible Conduct in Research” program.
BMB Seminar & graduate student journal club	1 - 5	Formal scientific research lectures are weekly in BMB seminar by visiting scientists, UNMC faculty and graduate students. At the weekly graduate student journal club students take turns presenting and discussing modern research articles. Attendance required for BMB students.
Comprehensive exam	2	To achieve “doctoral candidate” status, students are required to complete a comprehensive exam by end of year 2. The students write and defend a mock research proposal on a topic that is distinct from their own dissertation research area. Through this exercise students are taught how to develop scientific hypothesis and objectives, write proposals to obtain external research dollars to support their research and how to answer questions orally and “think on their feet”. To pass the exam, students must write and present their proposal clearly and demonstrate a mastery of the principles of BMB. A special four member faculty committee administers the exam; selected based on exam-topic expertise.
Teaching Practicum course	1 or 2	GCBA 806 Teaching Practicum: obligations of faculty members, the components of successful learning experiences, effective teaching techniques and development/functions of teaching portfolios are discussed. Required for all SB+B fellows.
SB+B research meeting	1 - 5	The research groups of SB+B faculty attend a monthly meeting and give informal research presentations. This creates a community that the GAANN students will be able to identify with, fosters a better appreciation for the breadth and nature of approaches to SB+B research, and increases familiarity with the interests and personalities of other researchers. Required for all SB+B fellows.
Supervised teaching experience	2 - 3	Each GAANN fellow will be required to provide two lectures in BIOC 850 and serve as a teaching assistant for one semester at the University of Nebraska at Omaha (UNO) for an undergraduate course.
Doctoral Research	1 - 5	Doctoral research is a major component of graduate training and includes the first-author publication of at least two major research articles by the student. All or part of the student’s doctoral research would include a SB+B component. Completion and defense of the thesis dissertation is the final requirement of the PhD

The required components of the SB+B GAANN training program are supplemented with several other important opportunities for professional development:

• Midwest Student Biomedical Research Forum
  

  An annual research forum features talks and posters by graduate students in the region and provides an opportunity for students to present and receive feedback on their research from faculty and students in a diverse range of scientific fields.

• National Meetings
  

  Fellowship support will allow fellows to present talks and/or posters at national meetings. This will provide students with opportunities to present and receive feedback on their research from faculty and students in their field, as well as the opportunity to “network” and make contacts with potential employers and/or collaborators at other institutes.
  
  Some examples include...
  
  - American Crystallographic Association Meetings
  - Protein Society Meetings
  - Biophysical Society Meetings
  - and many others.

As expected at a prominent research university, existing courses at UNMC provide the opportunity to develop the technical and philosophical expertise needed to reach a high level of achievement. Additional coursework can be taken by graduate students to tailor the program of study to the student’s career goals, in consultation with a student’s advisor and supervisory committee. A detailed academic guide and “BMB Graduate School Survival Kit” are available for faculty and students on the departmental web site (www.unmc.edu/dept/biochemistry; under “Education”).

Facilities

Here is a list of participating laboratories and major equipement that are available to SB+B students.

• X-ray crystallography
  

  R-AXIS IV imaging plate X-ray detector systems, FRE Rigaku SuperBright rotating anode X-ray source with two Osmic confocal X-ray optics (MicroMax optic for maximum brilliance & HiRes optic for crystals with large unit cells), & X-stream2000 cryostream.

• Protein expression & purification
  

  For making recombinant proteins in bacteria or yeast cells, & protein purification: New Brunswick BF-4500 fermentor, Sorvall RC-5C with continuous flow system, two New Brunswick, Innova 44 & 44R stackable bacterial incubator shakers, set at 30 & 37 ºC, & AKTA Explorer & FPLC chromatography systems.

• Crystal screening & growth
  

  For crystallization of biological macromolecules: Mikron stereomicroscope system with digital camera, Molecular Dimensions RuMed crystallization incubators, Art Robbins Phoenix for robotic setup of nanoliter scale crystallization trays & RockImager automated crystal imaging robot coupled to a Tecan Liquid Handler for the optimization of crystal growth. A temperature controlled Protein Solutions DynaProMS instrument & Agilent FPLC equipped with a Wyatt MiniDawn static light scattering instrument & Optilab DSP for light scattering studies to assess quality of protein samples for crystallization & to understand stoichiometry of complexes.

• NMR spectroscopy
  

  Varian unity-INOVA 600 MHz NMR spectrometer, including shielded superconducting magnet, console, high performance waveform generator, triple-axis gradients, a 5 mm (1H, 13C, 15N) XYZ PFG triple-resonance probe, a 5 mm Penta probe, and cryoprobe. There is also a Varian unity-INOVA 500 MHz NMR spectrometer.

• Atomic force microscopy (AFM)
  

  MultiMode SPM and NanoScope IV microscopes are equipped with a fluid cell capable of performing imaging samples in air and liquid. One of the systems has been upgraded with the PicoForce module for force measurements in the pico Newton range. A molecular puller AFM (MFP-3, Asylum Research) for force spectroscopy experiments.

• Biophysical chemistry
  

  Calorimetric equipment for complete thermodynamic analysis: Microcal Omega & MCS isothermal titration calorimeters, MC2 and VP-DSC differential scanning calorimeters, Shimadzu TGA-50 thermogravimetric, DSC-50 analyzers & Anton Paar DMA-60 densitometer to measure volume changes. Other complementary equipment includes: Aviv UV/Vis, Fluorescence, circular dichroism spectrophotometers to measure secondary structure, & acoustical interferometer to measure macromolecular hydration. Beckman ProteomeLab XL-I analytical ultracentrifuge with a 4-place titanium rotor (An-60 Ti) and 8-place titanium rotor (An-50 Ti) measures molecular size & stoichiometry.

• Computational chemistry & bioinformatics
  

  The Center facilitates the integration of the biocomputing/informatics disciplines with the life sciences and coordinates cross-campus and state-wide efforts in bioinformatics, chemoinformatics, pharmacoinformatics, computational chemistry, and computational biology.

Participating Faculty

Students will interview with at least 5 faculty members and then perform three 6 week lab rotations in laboratories associated with the SB+B training program and then chose a laboratory to perform their thesis research. The participating faculty and a brief summary of their research interests and available projects are listed below:

Surinder K. Batra, Professor, Biochemistry and Molecular Biology.
Email: sbatra@unmc.edu

Research focus is on the structure/function relationship of mucins (in particular MUC4) that are highly glycosylated proteins. The overall objectives are to define the role of mucins under normal and pathological conditions, based on their dysregulated expression, presence of unique domains and aberrant glycosylation. Interactions of mucin domains with adhesive and anti-adhesive molecules are being studied using biochemical and will include biophysical techniques such as X-ray crystallography and nuclear magnetic resonance (NMR). Structural experiments would be in collaboration with Dr. Borgstahl and/or Dr. Sorgen. Taken together, the results obtained will form the basis for the development of diagnostics and therapeutics against cancer.

Elliott Bedows, Associate Professor, School of Allied Health Professions.
Email: ebedows@unmc.edu

Our lab has been studying the structure function relationships of gonadotropins, all of which act thru a G protein-coupled receptors. Different gonadotropin analogs selectively activate various combinations of signal transduction pathways following ligand binding, but the details of how this occurs is unknown. Elucidating the receptor structure and testing for differential signaling obtained when ligands are bound to the receptor would provide insight into the mechanism of gonadotropin function. This project will utilize state-of-the-art methods such as NMR, surface plasmon resonance (SPR), and analytical ultracentrifugation towards achieving its goals.

Gloria E. O. Borgstahl, Associate Professor, Eppley Cancer Institute.
Email: gborgstahl@unmc.edu

We are working to gain a molecular understanding of the repair of double-stranded DNA breaks by homologous recombination in humans. The specific objectives are to study the interactions of DNA repair factors (Replication protein A, Rad51 and Rad52) at the molecular level using dynamic/static light scattering, SPR, computational chemistry and X-ray crystallography. The results of these studies will help us to design therapies to treat and prevent cancer.

Tatiana K Bronich, Research Associate Professor, Pharmaceutical Sciences.
Email: TBronich@unmc.edu

Research interests are in the area of self-assembling polymer materials and their applications in nanomedicine. Of special interest is the design and study of novel types of functional materials based on complexes formed between block ionomers, oppositely charged polymers and low molecular weight amphiphilic molecules. Detailed examination of the physical properties of these nanostructures and their subsequent physical and chemical manipulation is allowing for their development in many broad areas, such as drug delivery and molecular imaging.

Pi-Wan Cheng, Professor, Biochemistry and Molecular Biology.
Email: pcheng@unmc.edu

Glycobiology is the research focus of the lab. One area of research is to determine the active site of a glycosyltransferase by x-ray crystallography with a goal of identifying small molecule inhibitors to treat patients with chronic lung mucus hypersecretory diseases. Another area of research is to study carbohydrate and lectin interactions by calorimetry, ultracentrifugation, atomic force microscopy, NMR, and SPR with the goal of identifying inhibitors to prevent/treat metastatic cancers.

Judith K. Christman, Stokes-Shackleford Professor and Chair, Biochemistry and Molecular Biology.
Email: jchristm@unmc.edu

We are studying interactions of enzymes involved in DNA and RNA methylation (Dnmt1 and Dnmt2) with novel inhibitors and the role of interaction of de novo methyltransferases (Dnmt3a,3b) with the base excision repair enzyme thymine glycosylase. The objectives are to study these interactions at the molecular level using surface plasmon resonance, analytical centrifugation and X-ray crystallography. The results obtained in these studies will provide the basis for understanding the role of Dnmt's in gene silencing and preserving genomic stability, for understanding how these activities are regulated and will lead to the development of therapeutics that enhance the cancer preventing role(s) of DNA methylation.

Pawel S. Ciborowski, Assistant Professor, Biochemistry and Molecular Biology.
Email: pciborowski@unmc.edu

Research explores the relationship between structure and function of proteins in normal and disease states using a proteomics approach. HIV-1 infected macrophage are used as a biological model for the following types of studies: function of cytoskeletal proteins during infection, biomarker discovery in neurodegenerative disorders and alterations in signaling pathways in infected macrophage in response to external stimuli such as opportunistic infection, clearing cell debris etc. Specific mass spectrometry techniques used will include: LC-MS/MS, MALDI-TOF and SELDI-TOF.

Michael A. Hollingsworth, Professor, Eppley Cancer Institute.
Email mahollin@unmc.edu

Basic research projects investigate the molecular mechanisms by which human pancreatic cancers are transformed and become malignant, including studies on macromolecules, such as Mucins, that contribute to the metastatic spread of pancreatic cancer. Structural studies employing NMR, and/or X-ray crystallography on signaling events; i.e. phosphorylation, involving the C-terminal tail of Mucin-1 will be performed through collaborative efforts with other investigators.

Alexander V. Kabanov, Professor, Pharmaceutical Sciences.
Email: akabanov@unmc.edu

Polymer nanomaterials that carry drugs, genes, and imaging agents are developed to diagnose and treat cancer and neurodegenerative diseases. To characterize nanomaterials fluorescence spectroscopy, dynamic light scattering, micro-electrophoresis, atomic force microscopy, etc. are used. Then in vivo methods are used to examine pharmacological responses and disease therapy. Thus, "tough" biological barriers have been successfully crossed, drug resistant cells killed and molecules delivered across membranes to the brain.

Robert E. Lewis, Professor, Eppley Cancer Institute.
Email: rlewis@unmc.edu

We are determining the mechanisms used by the molecular scaffolds KSR1 and KSR2 to regulate proliferative signaling via the Raf/MEK/ ERK kinase cascade. The specific objectives of this project are to determine the structural basis for ATP binding to KSR1 and KSR2 and to determine the biological consequences of ATP binding to the function of KSR1 and KSR2. Structural studies employing nuclear magnetic resonance (NMR), and/or X-ray crystallography will be performed through collaborative efforts with other investigators. The results of these studies will help us to design therapies that may be useful in the treatment of cancer and diabetes.

Ming Fong Lin, Professor, Biochemistry and Molecular Biology.
Email: mlin@unmc.edu

Research investigates molecular mechanisms of tyrosine phosphorylation signaling involved in prostate carcinogenesis. Specifically, molecular interactions between a prostate-specific protein tyrosine phosphatase and a receptor protein tyrosine kinase will be studied and correlated with biological outcomes. First, specific tyrosine residue(s) of the kinase that are substrates for the phosphatase will be identified using phosphoproteomics. Then, the interaction between synthetic phosphopeptides and the phosphatase will be studing using various state-of-the-art technologies, for example, ultracentrifugation, NMR, SPR and molecular modeling. Understanding these important molecular interactions that are involved in carcinogenesis will help us to develop targeted therapy.

Yuri L. Lyubchenko, Professor, Pharmaceutical Sciences.
E-mail: ylyubchenko@unmc.edu

We are working in three areas: genomics, proteomics and nanomedicine. In the genomics area the main objective is to unravel the role of the DNA dynamics at different levels in regulation of DNA recombination, repair and replication. The major goal of our proteomics program is to understand the molecular mechanism of the protein misfolding phenomenon. In our nanomedicine program, the use of novel nanoimaging approaches to repair defective machines or to replace them with artificial nanosystems is an ultimate goal. Methods include atomic force microscopy (AFM) for single-molecule, dynamic-, nanoscale-imaging and to measure intermolecular forces of biological macromolecules; single molecule fluorescence microscopy and fluorescence correlation spectroscopy.

Luis A. Marky, Professor, Pharmaceutical Sciences.
Email: lmarky@unmc.edu

Research focuses on the energetic and hydration contributions of nucleic acid conformation and interactions. We are currently investigating the folding/unfolding of nucleic acid complexes of biological relevance, including triplexes, G-quadruplexes, i-motifs, three- and four-arm junctions, and their interaction with drugs and proteins. We are also optimizing oligonucleotide-based reagents for the targeting of genes and their products. The laboratory uses state-of-the-art instrumentation in a variety of biophysical techniques, such as differential scanning and isothermal titration calorimetries; UV, fluorescence and circular dichroism spectroscopies; and density and acoustical techniques.

Richard G. MacDonald, Professor, Biochemistry and Molecular Biology.
Email: rgmacdon@unmc.edu

Our laboratory studies the role of the insulin-like growth factor II/mannose 6-phosphate receptor (IGF2/MPR) in cancer. The IGF2/MPR mediates growth repression in most cells through binding an array of ligands--the growth factor IGF-II, the growth inhibitor transforming growth factor-beta, and many glycoproteins, including lysosomal enzymes, that have M6P groups. Defects in the M6P/IGF2R that interfere with these ligand-binding functions contribute to cancer. Structure-function analysis of the ligand binding activity using SPR analysis of the M6P/IGF2R is under way with deletion, truncation, and point-mutated forms of the receptor. Small-molecule inhibitors and stimulators of M6P/IGF2R dimerization and function are being analyzed by anayltical ultracentrifugation and ligand binding for potential use in anti-cancer therapy.

Youri I. Pavlov, Associate Professor, Eppley Cancer Institute.
Email: ypavlov@unmc.edu

We are working to understand the mechanisms of DNA replication and repair and replication in eukaryotes. The specific objectives are to study the dynamics of proteins at replication fork during normal cell division and when cells are exposed to carcinogens. We use genetic, biochemical, and structural approaches. We collaborate with Dr. Borgstahl and Dr. Tahirov to study three-dimensional structures of proteins involved in DNA metabolism using X-ray crystallography.

Angie A. Rizzino, Professor, Eppley Cancer Institute.
Email: arizzino@unmc.edu

Our research focuses on the molecular mechanisms that control the transcription of genes which are critical for mammalian development and cancer. The intramolecular interactions between different domains of transcription factors, which contribute to the function of transcription factors, are being studied. How subtle changes in the conformation of transcription factors influence their affinity for DNA and their interaction with other proteins will be explored. In addition to structural analyses using X-ray crystallography, which will involve collaborative efforts with other investigators, the effects of amino acid substitutions on transcription factor phosphorylation, DNA binding and ability to activate gene expression will be determined.

Simon Sherman, Professor, Eppley Cancer Institute.
Email: ssherm@unmc.edu

Computational chemistry and biophysical methods are used to study the structures and functions of biological macromolecules. Specific methodologies applied to proteins and peptides include molecular modeling, molecular dynamics simulations, conformational NMR analysis, QSAR analysis and methods of bioinformatics. This better understanding of the molecular basis of structure-functional relationships will allow us to perform structure-guided drug design.

Paul L. Sorgen, Assistant Professor, Biochemistry and Molecular Biology.
Email: psorgen@unmc.edu

Research focus is to understand how cell-to-cell communication mediates vitally important processes such as impulse propagation, regulation of cell growth, and organ development. The specific objectives are to investigate intra- and intermolecular interactions that define the structure of the major cardiac gap junction protein connexin43 during pH-mediated channel opening and closing. The tools used include NMR, SPR, analytical ultracentrifugation, and isothermal titration calorimetry (ITC). By understanding the structural bases of Cx43 regulation, it may become possible to design rational drugs to modulate gap junction communication that has been altered due to disease and ischemia injury.

Tahir H. Tahirov, Professor, Eppley Cancer Institute.
Email: ttahirov@unmc.edu

We study atomic resolution structures of macromolecular complexes involved in various stages of gene expression and DNA replication using X-ray crystallography. Our goal is to understand how the disease-related abnormalities interfere with the function of these complexes.

Gregory S. Taylor, Assistant Professor, Biochemistry and Molecular Biology.
Email: gstaylor@unmc.edu

My laboratory studies the myotubularin family of phosphoinositide phosphatases. Mutated in human neuromuscular developmental disorders, the myotubularins function to regulate phosphoinositides, which are key lipid signaling molecules involved in cellular membrane trafficking processes. Our specific objectives are to understand the structural elements that mediate interactions between myotubularin family proteins and control their function using X-ray crystallography and NMR-based approaches. The results of these findings will provide a basis for developing therapies for the treatment of human neuromuscular diseases.

About Omaha, NE

The University ofNebraska Medical Center is located in Omaha, NE. Omaha has a population around 800,000 and is on the Missouri river. It has all of the usual activities and services of any large sized US city with a small town atmosphere. For more detailed information about Omaha, please see theOmaha Chamber of Commerce website.

Housing

A variety of on-campus and off-campus housing options are available. For students with families and single graduate students, student housing is a popular choice. All rental units are located on the UNMC campus, within a short walking distance to all campus buildings. Properties consist of one, two and three bedroom units. Maintenance and campus security are available 24 hours a day. Leases are based on the academic year. Parking is provided. All rental agreements are made through the Business Services Department, Rental Property Management. UNMC just finished work on the crown jewel of student apartments. They are located at the east end of the Student Life Center parking lot. Prices run from $550 for a one bedroom and $750 for a two bedroom apartment. For additional information, contact Esther Collins at (402) 559-5201 or ecollins@unmc.edu A listing of off-campus housing is available online from the Omaha World Herald at Omaha.com. Students that choose to live off campus live near UNMC and in apartments in other areas of the city. There are a few apartment buildings between 38th and 36th Streets and between Farnam and Jones Streets that are reasonably priced and are located in a relatively safe part of the city and you can still walk to campus. Anything north, south, and especially east of these blocks is probably not the best of neighborhoods. Apartments that fit your requirements and price range can be found throughout Omaha. There are many apartments and homes to rent between the UNMC campus and 72nd Street. Drive times are only about 10 minutes and the neighborhoods are nice. As you go further west into Omaha, the drive time increases limiting trips home between experiments. Some graduate students even own their own houses.

Events in Omaha

Omaha has numerous attractions. We are home to the College World Series each June. We are also home of the Henry Doorly Zoo, the Orpheum Theatre, the Joslyn Art Museum, and the Durham Western Heritage Museum. The Omaha Royals, the AAA affiliate of the Kansas City Royals play each summer at Rosenblatt Stadium. Omaha has a Division 1 college hockey team in the University of Nebraska-Omaha Mavericks. The Qwest Center has held numerous concerts in the past couple of years. Other events include the annual Summer Arts Festival each summer and Jazz on the Green at the Joslyn Art Museum each fall. We also have the Old Market area in downtown Omaha for great shopping and dining. In 2006, Omaha will host the Division 1 Women's Volleyball Championship December 14-16 at the Qwest Center. In the spring of 2008, the First and Second Rounds of the Division 1 Men's Basketball Championship will be held March 20 and 22 at the Qwest Center. The Qwest Center will also host the U.S. Olympic Swimming Trials for the 2008 Olympics in Beijing, China in the summer of 2008.