Department: Biochemistry

Telomeres are nucleoprotein complexes that protect chromosome ends and shorten with cell division and aging. We are interested in how telomere shortening influences cancer, stem cell function and genomic stability. Telomerase is a reverse transcriptase that synthesizes telomere repeats and is expressed in stem cells and in cancer. We have found that telomerase also regulates stem cells and we are pursuing the function of telomerase through diverse genetic and biochemical approaches.

I closed my laboratory when I retired in 1998. I continue to do research, chiefly in collaboration with Franc Avbelj, on problems of protein folding energetics, especially peptide backbone solvation, and to write reviews.

Function of Hedgehog proteins and other extracellular signals in morphogenesis (pattern formation), in injury repair and regeneration (pattern maintenance). We study how the distribution of such signals is regulated in tissues, how cells perceive and respond to distinct concentrations of signals, and how such signaling pathways arose in evolution. We also study the normal roles of such signals in stem-cell physiology and their abnormal roles in the formation and expansion of cancer stem cells.

For about 10 years until 2000, my lab's research activities were focused on the mechanism of recombinational repair of double-strand breaks in DNA. We focused our efforts on two model systems: one involved the repair of restriction enzyme cleavages at specific mammalian chromosomal loci and the second explored the biochemical properties of purified yeast Rad51 protein, an essential catalyst for synapsing the broken ends of DNA with an intact homologue of that sequence. We also explored the ro..

Dr. Brown's research group uses diverse experimental and computational methods to investigate the logic and mechanisms that control a genome's expression program. The Brown laboratory is systematically characterizing the genetic scripts that control the expression of our genes, in normal development and physiology and in diseases like cancer, with a particular focus on post-transcriptional regulation. The Brown lab also develops strategies and assays for early detection and diagnosis of cancer.

My primary interest is to understand the flow of information from the genome to the phenotype of an organism. This interest includes predicting the structure and function of genes and proteins from their primary sequence, predicting function from structure and finally simulating protein folding and ligand docking. These goals are the same as the goals of molecular biology, however, we use primarily computational approaches.

Our laboratory focuses on understanding how cells respond to DNA damage. Our research currently involves areas that interact with each other: repair of radiation damage, and transcriptional responses to DNA damage.

Rhiju Das strives to predict how sequence codes for structure in proteins, nucleic acids, and heteropolymers whose folds have yet to be explored. The Das group uses new computational and experimental tools to tackle the de novo modeling of protein and RNA folds, the high-throughput structure mapping of riboswitches and random RNAs, and the design of self-knotting and self-crystallizing nucleic acids.

We are using Saccharomyces cerevisiae and Human to conduct whole genome analysis projects. The yeast genome sequence has approximately 6,000 genes. We have made a set of haploid and diploid strains (21,000) containing a complete deletion of each gene. In order to facilitate whole genome analysis each deletion is molecularly tagged with a unique 20-mer DNA sequence. This sequence acts as a molecular bar code and makes it easy to identify the presence of each deletion.

My lab has two main goals: to understand mitotic regulation and to understand the systems-level logic of simple signaling circuits. We often make use of Xenopus laevis oocytes, eggs, and cell-free extracts for both sorts of study. We also carry out single-cell fluorescence imaging studies on mammalian cell lines. Our experimental work is complemented by computational and theoretical studies aimed at identifying the design principles of regulatory circuits.

Our lab engineers proteins and small-molecule drugs at atomic resolution through a combination of structural calculations and combinatorial library synthesis. Our goal is to elucidate predictive principles by which novel shapes and catalytic properties can be conferred accurately on designed polypeptides.

Our research is aimed at understanding the chemical and physical behavior underlying biological macromolecules and systems, as these behaviors define the capabilities and limitations of biology. Toward this end we study folding and catalysis by RNA, as well as catalysis by protein enzymes.

How are genes regulated to construct a developmental program? How do signals received from other cells change the program and coordinate it for multicellular development? The approach taken by our laboratory group to answer these questions utilizes biochemistry and genetics; genetics to isolate mutants that have particular defects in development and biochemistry to determine the molecular basis of the defects. We study swarming in Myxococcus xanthus that builds fruiting bodies.

Research interests in this laboratory lie at the interface of chemistry and medicine. For the past several years, we have investigated the catalytic mechanisms of modular megasynthases such as polyketide synthases, with the concomitant goal of harnessing their programmable chemistry for preparing new antibiotics. Recent accomplishments include methods for heterologous production of polyketides; genetically reprogrammed biosynthesis of anthraquinones and polypropionates; and chemo-biosynthesi..

- Lung development and stem cells - Neural control of breathing - Lung diseases including lung cancer - New genetic model organisms for medicine

We study Herpes simplex virus type 1 as a model eukaryotic chromosome for the analysis of eukaryotic DNA replication and recombination

The goal of our research is to elucidate the molecular mechanisms by which proteins are targeted to specific membrane compartments. How do transport vesicles select their contents, bud, translocate through the cytoplasm, and then fuse with their targets? We study the Ras-like Rab GTPases--how they serve as master regulators of all receptor trafficking events. We also study how cells acquire cholesterol from the diet and from LDL.

We are working to elucidate the biochemical and cell biological principles that govern signaling pathways that sit at the intersection between developmental biology and cancer. Our toolkit combines bulk biochemical techniques, such as cell-free reconstitution, with microscopy using novel optical probes to study the dynamics of signal propagation in cells. We strive to develop novel strategies for the manipulation of these pathways for cancer therapies and applications in regenerative medicine.

The general research interest of this laboratory is the molecular basis of cell motility. We have three specific research interests, the molecular basis of energy transduction that leads to ATP-driven myosin movement on actin, the biochemical basis of the regulation of actin and myosin interaction and their assembly states, and the roles these proteins play in vivo, in cell movement and changes in cell shape.

We study the process of cell division. Our research is focused on understanding how chromosomes are segregated during mitosis and how cells divide during cytokinesis.

We study the interactions between infectious bacteria and the human host cell actin cytoskeleton. Listeria monocytogenes and Shigella flexneri are unrelated food-borne bacterial pathogens that share a common mechanism of invasion and actin-dependent intercellular spread in epithelial cells. Our studies fall into three broad areas: the biochemical basis of actin-based motility by these bacteria, the biophysical mechanism of force generation, and the evolutionary origin of pathogenesis.

The chemistry and biology of the unusual plastid organelle, the apicoplast, in malaria parasites