Department: Chemical and Systems Biology

Our lab uses chemical, biochemical, and cell biological methods to study protease function in human disease. Projects include: 1) Design and synthesis of novel chemical probes for each of the primary protease families. 2) Understanding the role of proteolysis in the life cycle of the human parasites, Plasmodium falciparum and Toxoplasma gondii. 3) Defining the specific functional roles of proteases during the process of tumorogenesis. 4) In vivo imaging of protease activity

Our laboratory combines synthetic chemistry and developmental biology to investigate the molecular events that regulate embryonic patterning, tissue regeneration, and tumorigenesis. We are currently using genetic and small-molecule approaches to study the molecular mechanisms of Hedgehog signaling, and we are developing chemical technologies to perturb and observe the genetic programs that underlie vertebrate development.

The use of genetic, biochemical and chemical approaches to understand the DNA damage-induced cell cycle checkpoints and the processes that contribute to maintenance of genomic stability.

Our focus is on building computational models of complex biological processes, and using them to guide an experimental program. Such an approach leads to a relatively rapid identification and validation of previously unknown components and interactions. Biological systems of interest include metabolic, regulatory and signaling networks as well as cell-cell interactions. Current research involves the dynamic behavior of NF-kappaB, an important family of transcription factors.

Developing new mass spectrometry-based experimental and computational tools that advance the field of proteomics, and applying them to a variety of important biomedical paradigms, including cancer, aging, and stem cell biology.

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.

Structure, dynamics and function of proteins involved in transport and regulatory processes; high resolution nuclear magnetic resonance studies of conformational transitions and protein folding; study of the mechanism of action of the trp-repressor, ankyrin-domain proteins and the development of programs to calculate protein solution structure

Survival in changing environments requires the acquisition of new heritable traits. However, mechanisms that safeguard the fidelity of DNA replication often limit the source of such novelty to relatively modest changes in the genetic code. Thus, the acquisition of new forms and functions is thought to be driven by rare variants that occur at random, and are enriched during times of stress. We have begun to study an intriguing alternative hypothesis: that intrinsic links between protein folding ..

Mechanisms of Aging in C. elegans and humans.

Structure, function and physiology of adrenergic receptors.

We explore angiogenesis, cancer genomics, intestinal stem cells, and hepatic glucose metabolism. Angiogenesis projects include endothelial miRNA and GPCR ko mice, blood-brain barrier regulation, stroke therapeutics and anti-angiogenic cancer therapy. Intestinal stem cell projects use primary intestinal culture and mouse genetics to study injury-inducible vs homeostatic stem cells. We use primary organoid cultures of diverse tissues for oncogene functional screening and therapeutics discovery.

CELLULAR INFORMATION PROCESSING The main problem in signal transduction is to understand how different receptor-stimuli specifically control diverse cell functions. We are using automated microscopy, live-cell fluorescent biosensors and perturbations of predicted signaling proteins to systematically dissect signaling networks. This allows us to identify signaling modules and to elucidate and ultimately model the flow of cellular information.

Beverly Mitchell's research relates to the development of new therapies for hematologic malignancies, including leukemias and myelodsyplastic syndromes. She is interested in preclinical proof of principle studies on mechanisms inducing cell death and on metabolic targets involving nucleic acid biosynthesis in malignant cells. She is also interested in the translation of these studies into clinical trials.

Two areas: 1. Using rationally-designed peptide inhibitors to study protein-protein interactions in cell signaling. We focus on protein kinase C (PKC)-mediated signal transduction and on mitochondrial dynamics in several disease models. 2. Using small molecules (identified in a high throughput screens and synthetic chemistry) as activators and inhibitors of aldehyde dehydrogenases, a family of detoxifying enzymes, we study their involvement in normal cells and in models of human diseases.

Insulin is one of the primary regulators of rapid anabolic responses in the body. Defects in the synthesis and/or ability of cells to respond to insulin results in the condition known as diabetes mellitus. To better design methods of treatment for this disorder, we have been focusing our research on how insulin elicits its various biological responses.

A central aim of the burgeoning field of systems biology is to understand the principles governing genetic control networks. I believe finding the principles underlying genetic circuits will occur through detailed studies and then comparisons of several natural systems. Due to its extensive development as an experimental system, our favorite model, the budding yeast cell cycle, is poised to become central to this enterprise.

The Teruel Lab uses a combination of engineering and biological approaches including high-throughput screening of RNAi and DNA construct libraries, targeted mass spectrometry, live-cell fluorescence microscopy, and bioinformatics to investigate the systems biology of cell differentiation and cell signaling with particular focus on uncovering the molecular mechanisms underlying insulin resistance, diabetes, and obesity.

We employ an interdisciplinary approach to studies of biological systems, combining synthetic chemistry with biochemistry, cell biology, and structural biology. We invent tools for biology and we are motivated by approaches that enable new experiments with unprecedented control. These new techniques may also provide a window into mechanisms involved in maintaining cellular homeostasis. Protein quality control is a particular interest at present.

We analyze the mechanisms by which mammalian cells adapt to environmental changes, such as exposure to foreign chemicals, hypoxia, or hormones, by altering the transcription of specific sets of genes. We use both biohchemical and genetic approaches and many techniques in molecular and cellular biology. See: http://www.stanford.edu/group/whitlock/

Research in our lab focuses on mechanisms of epigenetic regulation in differentiation and development. In particular, we are studying the function of histone modifying enzymes in embryonic stem cell self-renewal and in early cell fate decisions. We are interested in the role of chromatin modifications in establishment and maintenance of gene expression patterns during normal and pathological development, and in nuclear reprogramming.