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Laboratory of Molecular Biology

Research

The Laboratory of Molecular Biology uses genetics, molecular biology, cell biology, and molecular modeling to examine and solve a broad range of important biological problems. In the Molecular Biology Section, one major program is directed at designing, producing, and testing new drugs (immunotoxins) to treat cancer. These drugs are genetically modified forms of Pseudomonas exotoxin A that are targeted to cancer cells by Fv fragments of antibodies. Five recombinant immunotoxins that have been developed in the laboratory are now in clinical trials. Two of these have activity in hairy cell leukemia, chronic lymphocytic leukemia, Hodgkin's disease, and other malignancies. Design of these molecules is greatly aided by molecular modeling. A new bioinformatics group collaborates with Byungkook Lee in the Molecular Modeling Section to discover new genes in prostate and breast cancer as targets for immunotherapy.

The Clinical Immunotherapy Section group runs clinical trials of recombinant immunotoxins in patients with cancer and studies issues related to these Fv-toxin molecules in the lab. Ongoing clinical trials include targeting CD22 and CD25 in patients with leukemia, lymphoma, and Hodgkin's disease with the recombinant immunotoxins BL22 and LMB-2, both of which have induced complete remissions; and targeting the antigen mesothelin on pancreatic and ovarian cancers and mesothelioma (carcinomas). Laboratory projects deal with mechanisms of toxin effectiveness and action, and also study mechanisms and prevention of toxicity to normal tissues.

The Biotherapy Section group studies the structure and function of Pseudomonas exotoxin (PE) and applies this knowledge to the design of recombinant immunotoxins and vaccine proteins. An immunotoxin directed to CD22 is currently being evaluated for the treatment of B cell malignancies. A chimeric protein composed of nontoxic PE and the adhesion protein pilin is being developed as a vaccine to prevent the establishment of Pseudomonas infections in cystic fibrosis patients. In addition, the virulence of Pseudomonas aeruginosa is studied by characterizing the interaction of various exoproducts (such as toxins and proteases) with polarized epithelial cells and by monitoring regulation in response to iron deprivation. In low iron, Pseudomonas expresses two novel small non-coding RNAs that down-regulate the expression of iron storage genes.

Researchers in the Molecular Modeling Section (1) study the structure of globular protein molecules and the forces that determine the structure, stability, and interaction of these molecules, (2) design mutations that will alter/improve properties of a class of anticancer immunotoxins and of other specific protein molecules, and (3) analyze the expressed sequence tag (EST) DNA sequence database to discover genes that are specifically expressed in a particular organ or tumor. The product of such genes can potentially be used as a target for delivery of antitumor agents and for tumor imaging.

In the Molecular Genetics Section, investigators create and exploit genetically engineered mice as models for human cancer. Their research emphasizes the role of aberrant tyrosine kinase receptor signaling in the genesis and progression of cutaneous malignant melanoma. Mouse models of melanoma are currently being employed to rigorously assess genetic and environmental melanoma risk factors and to develop effectual sun protection strategies and antimelanoma therapeutics.

In the EGF Receptor Unit, the research focus is to identify and characterize transcription factors that regulate epidermal growth factor receptor (EGFR) expression. Investigators there have identified a novel repressor protein that decreases EGFR expression and represses the activity of viral promoters, including the HIV-LTR.

In the Gene Regulation Section, investigators have created mouse models of human diseases-including resistance to thyroid hormone, thyroid cancer, pituitary tumors, and dwarfism-by targeting mutations of thyroid hormone receptors to the gene locus. Using these knock-in mice, they investigate molecular events in the development and progression of these diseases. Current efforts are focused on elucidating aberrant molecular signaling pathways of mutant receptors underlying the carcinogenesis of thyroid cancer and on identifying molecular targets for prevention, diagnosis, and treatment.

In the Developmental Genetics Section, mechanism and control of gene transcription are studied with emphasis on structure, function, and dynamics of the transcription intermediates and their regulatory complexes. The latter include regulatory DNA-multiprotein complexes containing bifunctional transcription factors (gene activators and repressors), for example, cAMP receptor protein (CRP), Gal repressor (GalR) and histone like protein (HU). Another set of studies is focused on developing bacteriophage strains as agents in the diagnosis and curing of infections diseases in animals and humans.

The Biochemical Genetics Section is focused on studies of novel regulatory mechanisms and their use in complex regulatory circuits. In particular, the lab is currently focusing on small regulatory RNAs. Novel methods for finding these RNAs in genomes, studies on the roles they play in regulation and how they are themselves regulated, and studies of their mechanism of action are all of interest.

Investigators in the DNA Molecular Biology Section study ATP-dependent molecular chaperones, including members of the DnaK/Hsp70 and C1p/Hsp100 families, and the role of chaperones in protein degradation. They are currently exploring how the chaperone components of energy dependent proteases recognize substrates, catalyze protein unfolding, and translocate unfolded substrates from the chaperones to the proteolytic chambers of their associated proteases.

This page was last updated on 6/13/2008.