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- December 10 2013 at 2:30 PMWelcome CenterThe Office of the Vice President for Research is pleased to host the next Nano@Wayne seminar on Tuesday, December 10, 2013 from 2:30 to 3:30 p.m. in the Welcome Center Auditorium.The seminar is free and open to the entire campus community; a reception will immediately follow. The guest speaker will be Dr. Larry H. Matherly, professor of oncology in WSU's School of Medicine and the Karmanos Cancer Institute. He will present, "A new paradigm for cancer therapy: exploiting the proton-coupled folate transporter for targeted drug delivery to solid tumors." Abstract: Membrane transport is essential for antitumor activity of many chemotherapy drugs used for cancer. The Matherly laboratory has long focused on studies of transport processes for folates and folate analogs. These transporters include the ubiquitously expressed reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the high affinity folate receptors (FRs). RFC levels and function are primary determinants of cellular uptake of folate cofactors which are essential for nucleotide biosynthesis. RFC is also a critical determinant of uptake of classic antifolate drugs used for cancer therapy such as methotrexate and newer drugs typified by pemetrexed and pralatrexate. Based on patterns of tumor-selective expression and/or function of FRs and PCFT, recent emphasis has been on identifying novel cytotoxic drugs with selective cellular uptake by these other transporters over RFC. For instance, solid tumors such as ovarian carcinomas generally express high levels of FRs, and many solid tumors including lung, ovarian, and breast cancers abundantly express PCFT. Further, tumors are characterized by acidic microenvironments which would favor membrane transport by PCFT over RFC. Based on these concepts, novel 6- substituted pyrrolo- and thieno[2,3-d]pyrimidine compounds have been synthesized and identified with excellent PCFT- and/or FR transport activity and little to no transport activity by RFC. Experiments have established extraordinarily potent antitumor activities for many of these agents. Dr. Matherly’s talk will cover the rationale for this novel approach to tumor targeting with particular focus on PCFT as a means of for selective delivery of cytotoxic chemotherapy drugs.
- Continuous Peripheral Nerve Blocks
- December 11 2013 at 7:00 AMHarper University HospitalFeaturing Elie Chidiac, M.D. Presented by the WSU Department of Anesthesiology.
- Benign Lesions of the Larynx
- December 11 2013 at 7:30 AMHarper University HospitalFeaturing Dr. Sekhsaria. Presented by the WSU Department of Otolaryngology.
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Research interests in the Department of Biochemistry and Molecular Biology are diverse, allowing graduate students to choose from a broad spectrum of topics when picking a research lab. Regular interactions between students and faculty are facilitated with weekly departmental and student seminars, formal collaborations between research groups and a cooperative work environment that promotes discussion of research projects between students of different labs. Programs that cover the research performed in this department are described in detail below.
1. Structural Biology (Edwards, Gatti, Kovari, Stemmler, Wang, Yang)
Structural biology provides the framework for understanding how biomolecules function. The X-ray crystallographic component of the departmental Structural Biology program is at the leading edge in this field. The Wayne State’s Advanced Laboratory for Macromolecular Crystallography (ALMC), located in our department, is one of few laboratories in the world that possesses a high-flux X-ray generator capable of producing an X-ray beam that is 5 times stronger than conventional generators. Our department also participates in a state-funded program for developing a $13 million X-ray diffraction station at the Advanced Photon Source (APS) at the Argonne National Laboratories in Chicago. Research in the field of Nuclear magnetic resonance spectroscopy (NMR) provides a second component of our department’s Structural Biology program. The department has an impressive arsenal of NMR spectrometers at our disposal, providing students access to a 700 MHz, 600 MHz, 500 MHz and 400 MHz spectrometers (most with cryoprobes) for their research. In addition, the department participates in a state-funded program that allowed the recent purchase of a 900 MHz spectrometer, which will be located close to our university and available for our students to use. Current projects in the field of structural biology include:
- Regulation of mammalian blood clotting proteins.
- Metal and metalloid homeostasis regulation and transport proteins.
- Bacterial cell wall development.
- HIV-1 viral maturation events.
- Proteins that confer antibiotic resistance in bacteria.
- Flavoenzyme structure and function.
- Structural characterization of chaperones.
- Structure and function of histone methyltransferase in heart diseases
2. Cellular Metal Homeostasis and Drug Resistance
(Akins, Bhattacharjee, Edwards, Evans, Kovari, Lee, Lightbody, Mitra, Mukhopadhyay, Rosen, Stemmler, Vinogradov)
Cells have evolved pathways to control metal homeostasis and drug resistance in an attempt to maintain viability under normal and stress induced conditions. If one possesses a general understanding of these events, and the proteins that influence them, we can control dysfunctional processes in humans that lead to a variety of disorders. Research in these areas within our department include:
- Metal influx and efflux transporters, chaperones and the P-type ATPases.
- Mechanisms of transport and detoxification of metals and metalloids.
- Control of cellular oxidative stress.
- Heme and iron-sulfur cluster biosynthesis.
- Drug resistance conferred by HIV-1 protease mutants.
- Antibiotic resistance in gram-negative bacteria.
- Pathogenic fungal drug resistance mechanisms.
- Biochemical basis of immunodeficiency diseases.
3. Molecular Biology and Cancer
(Brooks, Edwards, Evans, Finley, Johnson, Needleman)
Cancer is a major global health problem that prevents a large number of humans from living a normal and healthy life. Disruption of normal homeostatic pathways leads to aberrant behavior in cells and this is at the heart of cancer. To make progress in fighting cancer, we must learn how cellular processes are regulated. Molecular biology is central to this enterprise, and it is the focus of a number of research groups in the Department. Research in molecular biology is ongoing in our department in the following areas:
- Estrogen receptor regulation of gene transcription.
- DNA synthesis pathways.
- Mitochondrial genetics.
- Cell cycle regulation pathways.
- Phosphorus chemistry.
- Regulation of gene transcription.
- Regulation of expression of ATPase genes.
- Relationship between gene expression and the assembly and activity of F-ATPase.
4. Molecular and Cellular Bioenergetics
(Ackerman, Brusilow, Edwards, Gatti, Lee)
Mitochondria are the source of metabolic energy for nearly all cellular activities. These complex organelles comprise proteins coded by their own genomes and by the nuclear genome, as well as a diverse array of complex lipids. The way in which the components are assembled into a functional unit remains a major question. The details of energy transduction via electron transfer remain an enigma, whose solution would yield a profound insight into one of the most significant components of eukaryotic metabolism. Finally, mitochondria play the major role in initiating apoptotic cell death, with enormous implications for embryonic development, central nervous system architecture and cancer. Current projects being carried out by researchers in the Department of Biochemistry and Molecular Biology include:
- Mitochondrial ATP synthase assembly.
- Structure and function of the E. coli proton-translocating ATPase/ATP synthase.
- Proteins involved in energy transduction in bacterial and eukaryotic membranes.
- Mitochondrial bioenergetics.
(Evans, Edwards Gatti, Mitra)
Nearly all of the metabolic activities that make up the life of the cell are carried out by proteins - enzymes and transport proteins. Enzymes catalyze an astonishing and diverse range of chemical transformations. A second set of important functional proteins are the membrane proteins that transfer molecules in and out of the cell. In addition to elucidating the biological activity of these proteins, researchers in the Department are also interested in the chemical mechanisms that they utilize to carry out this diverse array of activities. Some projects now in progress include:
- The multifunctional enzymes of pyrimidine biosynthesis.
- Thermophilic enzymes.
- Structure and mechanism of oxidative enzymes.
- Mechanisms of reactions catalyzed by flavoproteins.
- Molecular mechanisms of transport of soft metals and metalloids.
- Heavy metal detoxification (arsenic, lead, and other metals).