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Dr. Farnsworth - Principal Investigator/Program Director (Last, first, middle)


Dr. Farnsworth

: The research group, founded by Dr. Farnsworth in 1982, known as the “Program for Collaborative Research in the Pharmaceutical Sciences”, is in essence a natural products drug discovery group in which faculty in the following disciplines work together in attempts to discover new drugs in the area of cancer prevention, cancer treatment, treatment of hepatitis B, HIV and many other biological targets. These efforts have led to many patents and potential drugs being studied further at NCI, i.e., betulinic acid for melanoma, resveratrol for chemoprevention, and several others that in the RAID program at NIH. More recently Dr. Farnsworth has directed his efforts in the area of studying botanical dietary supplements, especially those that may improve women’s health, i.e. menopause, urinary tract infections, etc. This work is supported for five years (currently entering the fourth year) as a UIC/NIH Center for Research on Botanical Dietary Supplements. The activities range from botanical identification to chemical and biological standardization, to mechanism of action, to bioassay development and Phase I and Phase II clinical studies on two botanicals, red clover and black cohosh. Major research interests include: Isolation and structure elucidation of biologically active products from natural sources;. Predictive methods for discovery of biologically active compounds from plants, using computer analysis; Rational evaluation of folklore, ethnomedical, and traditional medicinal plants.

Dr. Franzblau

: Dr. Franzblau is director of the Institute for Tuberculosis Research. His research focuses on new drug discovery. This includes the evaluation of crude biological materials, such as plant extracts, for activity against the tubercle bacillus. In addition, new high throughput screening assays are being developed to allow efficient evaluation of large chemical libraries, as well as development of assays that may predict activity against non-growing or dormant/latent M. tuberculosis. This development, in turn, requires an understanding of the basic biology of the organism; to this end, the ability to assess the transcriptome, proteome, and metabolome to assist in this endeavor is being examined. These same assays will be utilized to help understand the mechanism of action of newly discovered, selective agents. The mechanisms of innate resistance of M. tuberculosis to ribosome-active agents are also examined, looking both at ribosome modification and in particular efflux mechanisms of innate resistance to macrolides and tetracyclines. Finally, novel drug delivery systems for TB agents are being investigated.

Dr. Mesecar

: The main focus of the Mesecar laboratory is the investigation of the role of protein dynamics and conformational change in molecular recognition and catalysis. A variety of technologies

from the fields of chemistry, biology, and physics such as, x ray crystallography, enzyme kinetics, isotope effects, synthetic organic chemistry, bioinformatics, computational chemistry, and molecular biology are utilized. The laboratory is currently pursuing four projects in the area of enzyme and receptor structure and function including: 1) "Molecular Movies" of enzymes under catalytic turnover. This involves mapping out the entire reaction coordinates of isocitrate dehydrogenase and trihydroxytoluene dioxygenase. 2) Understanding the structural and functional consequences of

genetically inherited point mutations in the human pyruvate kinase (PK) R isozyme that cause non-sphereocytic hemolytic anemia. The goal is to rationally design novel drugs that are targeted against the allosteric site of this isozyme so that it can be "kinetically rescued" and restored to proper function. 3) Determining the kinetic, chemical and structural mechanisms of enzymes involved in bioremediation of pentachlorphenol (PCP), 2,4 dinitrotoluene (DNT) and nitrobenzene (NB); The long-range goal of this project is to redesign the enzymes of these pathways to broaden their substrate repertoire to biodegrade currently "non biodegradable" compounds. 4) The small-molecule structure

elucidation of novel natural products that have been discovered via bioassay-guided fractionation methods based on Cancer Chemoprevention and AIDS prevention. The long term goal of this project is to acquire three-dimensional structural data that can be used as a basis to design new and more potent compounds for the purpose of cancer and AIDS prevention.



Additional Preceptor in Drug Discovery/Natural Products



Because their research areas overlap, their research summaries are given under the following heading:



Dr. Bolton - Tumor Cell Biology and Cancer Chemoprevention



Dr. Kozikowski –Neuropharmacology



Anticancer and Antimicrobial Chemotherapy



Dr. Gemeinhart

The Biomedical Polymer Science Laboratory investigates the response of biologic systems to polymeric biomaterials as they relate to cancer chemotherapy and tissue engineering. They are developing nanoscale polymeric devices that exploit the metastatic and invasive characteristics of a tumor for targeted delivery of conventional chemotherapeutic agents. These agents, such as camptothecin, cisplatin, and paclitaxel, can be very potent and effective, but are difficult to deliver safely using conventional drug delivery methodologies and can result in debilitating side effects. Targeting of conventional chemotherapeutics using nanoscale polymeric devices allows large quantities of insoluble and highly toxic agents to be delivered to the most active and intractable aspects of a tumor. Dr. Gemeinhart’s laboratory focuses on tumors of the central nervous system and pancreas, with preliminary work also being conducted on breast and ovarian cancer. They are currently investigating the mechanisms of cellular uptake of the nanoscale polymeric devices, cleavage and delivery of several chemotherapeutic agents, affect of nanoscale polymeric devices on multi-drug resistance, and the use of nanoscale polymeric devices for disease diagnosis. The Gemeinhart laboratory is also investigating the ability of polymeric systems to promote tissue regeneration and wound healing. They have identified biologic motifs that can be used to promote orientation and growth of specific cell types, and are currently investigating the exact cellular responses that are elicited by attachment of these cells to the extracellular matrix, a natural polymeric network that provides a substrate for cell binding, thereby activating specific cellular signaling events.

Dr. Mankin

:

The research in the Mankin laboratory is focused on understanding the mechanism of action of ribosome-targeted antibiotics. The sites of interaction of drugs with the ribosome are mapped using a combination of biochemical (RNA footprinting) and genetic (resistance mutations mapping)

approaches. Elucidation of the antibiotic binding site often leads to an understanding of which function of the ribosome is inhibited by the antibiotic. Furthermore, identifying possible resistance mutations reveals the nature of emerging mechanisms of drug resistance and opens venues for improving

pharmacological properties of the drugs by developing compounds that exhibit favorable activity against the resistant organisms

.



Dr. Neyfakh

: The research of Dr. Neyfakh’s group concentrates on the study of bacterial multidrug-efflux transporters involved in antibiotic resistance, and other antibiotic-resistance mechanisms. Dr. Neyfakh was the first to discover chromosomally-encoded multidrug transporters in bacteria. He identified the first inhibitors of these transporters and contributed to the understanding of the regulation of transporter expression, their physiological function, and the mechanism of drug recognition. Currently, his research is focused on identification of novel molecular mechanisms of intrinsic antibiotic resistance. He recently developed a novel method of identification of bacterial mutations leading to antibiotic hypersusceptibility. These mutations will identify the genes involved in antibiotic resistance, thus providing potential targets for potentiatiors of antibiotic activity.

Additional Preceptors in Anticancer and Antimicrobial Chemotherapy



Because their research areas overlap, their research summaries are given under the following headings:



Dr. Beck - Tumor Cell Biology and Cancer Chemoprevention



Dr. Chishti – Molecular Pharmacology and Cell Signaling



Dr. Franzblau - Drug Discovery/Natural Products



Dr. Gemeinhart - Anticancer and Antimicrobial Chemotherapy



Biopharmaceutics and Drug Delivery



Dr. Miele:

The Miele laboratory’s areas of expertise include design and development of peptide drugs, recombinant protein biopharmaceuticals, and gene therapy vectors; and target identification, using genomics and proteomics. Dr. Miele’s research interests are focused primarily on the Notch signaling network as a novel target for biopharmaceuticals. Notch signaling controls cell differentiation in a variety of cell types, including hematopoietic stem cells. Agonists and antagonists of Notch signaling are being developed to be used ex vivo to control the differentiation of human cells (for example, in applications involving the expansion and controlled differentiation of stem cells or in immunotherapeutic applications) and in vivo as biopharmaceuticals. His experience is complemented by four years at FDA/CBER, where he directed the Laboratory of Cell Biology and had significant review and policy responsibilities both for product characterization (in the Division of Monoclonal Antibodies) and for clinical trial design (in the Division of Clinical Trial Design and Analysis). Dr. Miele presently consults for several biotechnology and pharmaceutical companies on issues involving biopharmaceutical development and clinical testing.

Dr. Onyuksel

: Research in the Onyuksel laboratory focuses on several aspects of drug delivery, with a specific focus on parenteral drug delivery. Specific areas of interest include targeted delivery of therapeutic agents to cancerous or arthritic tissues to achieve decreased side effects and increased efficacy, formulation of water insoluble drugs in lipid based carriers such as micelles and liposomes for improved solubility and efficacy, delivery of peptide and protein drugs using phospholipid carriers for improved stability and circulation half life, and targeted delivery of radionuclides to breast cancer for enhanced imaging and early detection.

Dr. Rao

: Research in Dr. Rao’s laboratory focuses on understanding the molecular mechanism(s) underlying hormonal and neurotransmitter regulation of epithelial ion transport processes. These

studies impact our understanding of normal physiology as well as of pathological states ranging from infectious diarrheas to cystic fibrosis. A specific focus is the role of the cross-talk between different signaling systems, and the resultant post-translational modifications, such as protein phosphorylation

and dephosphorylation, involved in the regulation of epithelial ion transport. Current projects examine ion transport in gastrointestinal and mammary epithelia. Epithelia are multi-faceted and complex often

containing multiple isoforms of the same ion or solute transporter which are compartmentalized to different membranes and perform different functions. A number of epithelial transporters also serve as transporters for drugs, such as the H+-dependent dipeptide transporter. A recent collaboration with members of the Department of Pediatrics and the Department of Pharmacodynamics and Pharmaceutics examined the transport of cocaine across a model epithelial layer. These approaches to studying transport across polarized monolayers in conjunction with cellular signaling mechanisms will provide students the opportunity to understand the physiology of the epithelium both as a conduit and a barrier to nutrients and drugs.

Additional Preceptor in

Biopharmaceutics and Drug Delivery:



Because his research areas overlap, his research summary is given under the following heading:



Dr. Gemeinhart - Anticancer and Antimicrobial Chemotherapy



Structural Biology



Dr. Johnson

: Research interests in the Johnson laboratory include: Nuclear magnetic resonance studies of protein and peptide 3D structure; macromolecule ligand interactions; computer aided design and structural bioinformatics. Applications of this research are found in sickle hemoglobin, the coagulation proteases, structural studies of the cytoskeletal protein, spectrin, and mechanisms of antibiotic resistance. Computer aided molecular design of potential therapeutic agents. Current projects include NMR structure determination of spectrin domains, QSAR analysis of bacterial antibiotic potentiators, design of inhibitors for the coagulation cascade enzymes thrombin and factor Xa, and design of anti-sickling agents.

Additional Preceptors in

Structural Biology:



Because their research areas overlap, their research summaries are given under the following headings:



Dr. Kaplan - Molecular Pharmacology and Cell Signaling



Dr. Kozikowski – Neuropharmacology



Dr. Mesecar - Drug Discovery/Natural Products




PHS 398/2590 (Rev. 05/01) Page ______

Continuation Format Page


2014-07-19 18:44
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