Molecular, Cell, Developmental and Computational Biology

Diya Banerjee - dbanerjee@vt.edu

The normal development of multicellular animals requires that cells divide and differentiate at specific times. Abnormal development and disease states are often characterized by the inappropriate timing of cell fate and cell proliferation, e.g. as in cancer cell metastasis. How is the correct timing of cellular development controlled?  My lab uses the nematode worm, C. elegans, as a genetic model organism to discover and characterize the developmental clock genes that regulate the correct timing of cell fate determination and cellular development.

We have found that a number of developmental timing genes are homologs of circadian clock genes, which control daily cycles of physiology and behavior, such as the sleep/wake cycle.  We are testing the hypothesis that a similar molecular timing mechanism is used in both circadian and developmental timing pathways.  We are also investigating whether circadian genes interact with the developmental timing genes to exert environmental regulation of cellular development.  This line of investigation may lead to an understanding of how disruption of the circadian cycle in animals can lead to cancer.  Another thrust to our investigations focuses on the function of developmental timing genes on regulating neural development.

These studies together will lead to a fundamental understanding of how cellular differentiation is coordinated, and will offer insight into the etiology of diseases that can arise from disruption of normal developmental timing.

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Our current research centers on the molecular structure and biochemical functions of signaling transduction systems involved in the development of cancer and other human diseases. Our goal is to understand how protein domains transduce signals. Our laboratory employs a multidisciplinary approach to investigate these problems. We apply structural and functional tools including high field NMR spectroscopy, circular dichroism, various computer modeling and computational approaches, liposome binding assays, fluorescence spectroscopy and surface plasmon resonance spectroscopy to elucidate the molecular function of protein domains. We work at the interface of structural and cellular biology as well. Most of our research is conducted in collaboration with laboratories that focus on cellular biological aspects. This allows us to direct cell-based signaling and to correlate our in vitro studies in real biological systems.

Our laboratory is primarily interested in mitotic chromosome segregation and aneuploidy origin as a consequence of inaccurate chromosome segregation in somatic cells. Aneuploidy, the condition of a cell possessing an incorrect chromosome number, is well known for inducing severe pathological genetic syndromes (e.g. Down syndrome). In addition, aneuploidy plays a crucial role in tumor development and progression. We use a combination of live-cell imaging, quantitative microscopy, and protein inhibition to identify the cellular mechanisms responsible for accurate chromosome segregation, and to understand how changes in chromosome number are generated.

Our laboratory's research is focused on understanding the structure and function of Family 1 and Family 35 �-glycosidases with special emphasis on the mechanism of substrate specificity. To address questions related to substrate (i.e., aglycone) specificity, we use plant �-glycosidases as model systems because they represent extremes in substrate specificity even when there is high sequence identity among them, and plants synthesize and hydrolyze a large repertoire of �-glycosidic substrates. We are also studying the mechanism of specific interactions between plant beta glucosidases and other proteins and the biological significance of such interactions with special emphasis on response to biotic and abioitc stress.

Finkielstein Lab - Dr. Carla Finkielstein

A fundamental feature of all living organisms is the presence of two 24h-oscillating cyclic systems. One, the circadian clock, dictates the timing of many physiological responses and provides the cell with information that can be used to anticipate daily environmental changes. The second highly periodic system is devoted to controlling cell division and mediates the entry into and exit from the cell cycle. We now know that the proper timing of cell division is a major factor contributing to the regulation of normal growth and emerges as a fundamental process in the development of most cancers. Thus, my laboratory investigates some of the basic mechanisms that regulate cell cycle transitions, the contribution of environmental cues to ensure timely progression throughout it, and how both cycles are interlocked at the molecular level.Our work will contribute mechanistic insights to better our understanding of how signals are integrated into a precise clockwork that ultimately regulates cell growth, leading to the generation of novel therapeutic strategies for improving the efficacy of cancer treatment.

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Eukaryotic cell motility is required for tissue development, neuronal circuits, immunological surveillance, and tumor metastasis. My lab studies the biophysics and control of cell motility. Cells move through the rapid rearrangement of actin filaments. The combined force from many growing filaments pushes the cell membrane forward. Several actin binding proteins, including the Arp2/3 complex, capping protein, ADF/cofilin, profilin, tropomyosin, formins, and Ena/VASP, direct actin polymerization. My lab studies motility at an individual protein level using evanescent wave light microscopy and aims to reconstitute a model "leading cellular edge" from purified proteins while observing the organization of individual actin filaments.

Dr. Liwu Li Laboratory - Dr. Liwu Li

Innate immune response is our first line of defense against diverse microbial pathogens.  In addition, innate immunity regulates various inflammatory processes.  Alteration/aberration in innate immunity contributes to human diseases ranging from infection to atherosclerosis, diabetes and cancer.  Our research program aims to characterize the molecular and cellular signaling events controlling innate immunity response.  Several key molecules including interleukin-1 receptor associated kinases (IRAKs) are involved in innate immunity regulation.  1) We are examining the biochemical processes controlling IRAKs� modification, intra-cellular translocation and activation;  2) We are determining the downstream function of IRAK proteins;  3) We are studying the contribution of IRAKs to the pathogenesis of atherosclerosis and cancer using transgenic mice model.

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Florian Schubot Lab - Dr. Florian Schubot

Regulatory Mechanisms that govern expression of Type III Secretion systems in gram-negative bacterial pathogens

Some of the most potent pathogens utilize type III secretion systems: Yersinia pestis, enteropathogenic E.coli, Shigella flexneri, Salmonella enterica, and Pseudomonas aeruginosa. Since disruption of the type III secretion apparatus invariably leads to a significant attenuation of virulence, the structural and functional components of the secretion machinery are considered high value drug targets. Rather than targeting individual components of secretion machinery we have decided to focus our efforts on achieving a broader impact by suppressing the regulatory cascades that activate expression of multiple type III secretion-related genes.
The research in my laboratory is best described as structural microbiology. By way of protein crystallography in conjunction with microbiology we aim to decipher the molecular basis for virulence of bacterial pathogens. The gained insights will be applied towards reaching our ultimate goal: the structure-based development of potent antimicrobial agents.

Current research projects focus on cell cycle remodeling during the early development of the South African clawed frog Xenopus laevis. Specifically, my laboratory studies (1) the acquisition of DNA damage and DNA replication cell cycle checkpoints after the midblastula transition (MBT) of Xenopus development and (2) the engagement of a developmentally regulated program of cell death at the MBT. We are also collaborating with the Tyson group to develop and test mathematical models of the cell cycle.

member: Genetics, Bioinformatics and Computational Biology

Tholl Lab - Dr. Dorothea Tholl

The Tholl lab studies the biosynthesis, molecular regulation and physiology of plant volatiles and their function in plant environment interactions including insect attraction, defenses against herbivores and pathogens as well as oxidative stress protection. Current research projects focus on (1) terpene volatile metabolism and regulation in the model plant Arabidopsis thaliana, (2) dissection of the physiological and/or ecological functions of these volatiles in Arabidopsis, and (3) the evolution of volatile biosynthesis in Arabidopsis thaliana and related species.

Dr. Tyson's group builds computational models of the molecular mechanisms regulating various aspects of cell physiology, including cell growth and division, circadian rhythms, intra-cellular signal transduction pathways, and cell-cell signaling.

member: Genetics, Bioinformatics and Computational Biology

Our lab investigates the role of microtubules and microtubule-dependent motor proteins in cellular processes such as mitosis and meiosis. We use a variety of molecular, biochemical and biophysical techniques to understand how microtubules assemble, how motor proteins recognize cellular cargo, and how microtubule assembly and motor activity are regulated. We are also interested in cytoskeletal adaptations in extremophiles and identification of cytoskeletal-directed drugs.

The primary focus of our research is on understanding the subcellular organization of metabolic pathways. We are using the flavonoid biosynthetic pathway of Arabidopsis thaliana to examine the assembly and regulation of multienzyme complexes. We also collaborate with the Dean laboratory in the Department of Biochemistry on characterizing iron-sulfur cluster assembly in plants.

Xing Lab - Dr. Jianhua Xing

Our research interest is to understand the dynamics of biological systems at various time and length scales through theoretical analysis and modeling. At the molecular level, my current research focuses on understanding the mechano-chemistry of protein motors, and allosteric regulation mechanisms. At the systems level, we are interested in understanding the emerging properties of protein and genetic networks.