The Greider lab uses biochemistry to study telomerase and cellular and organismal consequences of telomere dysfunction. Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase. Telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. The lab has generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. The lab also is using the telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to stem cell loss. The lab has developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated.

Complexity in signaling networks is often derived from co-opting one set of molecules for multiple operations. Understanding how cells achieve such sophisticated processing using a finite set of molecules within a confined space--what we call the ""signaling paradox""--is critical to biology and engineering as well as the emerging field of synthetic biology. In the Inoue Lab, we have recently developed a series of chemical-molecular tools that allow for inducible, quick-onset and specific perturbation of various signaling molecules. Using this novel technique in conjunction with fluorescence imaging, microfabricated devices, quantitative analysis and computational modeling, we are dissecting intricate signaling networks. In particular, we investigate positive-feedback mechanisms underlying the initiation of neutrophil chemotaxis (known as symmetry breaking), as well as spatio-temporally compartmentalized signaling of Ras and membrane lipids such as phosphoinositides. In parallel, we also try to understand how cell morphology affects biochemical pathways inside cells. Ultimately, we will generate completely orthogonal machinery in cells to achieve existing, as well as novel, cellular functions. Our synthetic, multidisciplinary approach will elucidate the signaling paradox created by nature.

The Hey-Kyoung Lee Lab is interested in exploring the cellular and molecular changes that happen at synapses to allow memory storage. We use various techniques, including electrophysiological recording, biochemical and molecular analysis, and imaging, to understand the cellular and molecular changes that happen during synaptic plasticity. Currently, we are examining the molecular and cellular mechanisms of global homeostatic synaptic plasticity using sensory cortices as model systems. In particular, we found that loss of vision elicits global changes in excitatory synaptic transmission in the primary visual cortex. Vision loss also triggers specific synaptic changes in other primary sensory cortices, which we postulate underlies sensory compensation in the blind. One of our main research goals is to understand the mechanisms underlying such cross-modal synaptic plasticity. We are also interested in elucidating the events that occur in diseased brains. In collaboration with other researchers, we are analyzing various mouse models of Alzheimer's disease, especially focusing on the possible alterations in synaptic plasticity mechanisms.

The Gould Laboratory studies vesicles, known as exosomes and microvesicles (EMVs), that can be taken up by neighboring cells, completing a pathway of intercellular vesicle traffic. Our laboratory studies the molecular mechanisms of EMV biogenesis and uptake, and their contributions to cell polarity, cell-to-cell interactions, and intercellular signaling. We also examine the ways in which HIV and other retroviruses use the exosome biogenesis pathway for the formation of infectious virions, and the consequences of their EMV origin.

Research in the Claypool Lab is focused on defining how lipids and membrane proteins interact to establish and maintain normal mitochondrial function and how derangements in this complex relationship result in pathophysiology. We have demonstrated that yeast lacking tafazzin recapitulates all of the phospholipid abnormalities observed in human patients and many of the mitochondrial defects. Another major project in our lab focuses on the mitochondrial ADP/ATP carrier that is required for oxidative phosphorylation. Researchers are studying how these novel interactions help establish normal mitochondrial function, the biochemical details of these associations, and whether disturbances in these assemblies can contribute to mitochondrial dysfunction.

The research in the Svetlana Lutsenko Laboratory is focused on the molecular mechanisms that regulate copper concentration in normal and diseased human cells. To understand the molecular mechanisms of copper homeostasis in normal and diseased human cells, we utilize a multidisciplinary approach involving biochemical and biophysical studies of molecules involved in copper transport, cell biological studies of copper signaling, and analysis of copper-induced pathologies using Wilson's disease gene knock-out mice.

The Seth Blackshaw Lab uses functional genomics and proteomics to rapidly identify the molecular mechanisms that regulate cell specification and survival in both the retina and hypothalamus. We have profiled gene expression in both these tissues, from the start to the end of neurogenesis, characterizing the cellular expression patterns of more than 1,800 differentially expressed transcripts in both tissues. Working together with the lab of Heng Zhu in the Department of Pharmacology, we have also generated a protein microarray comprised of nearly 20,000 unique full-length human proteins, which we use to identify biochemical targets of developmentally important genes of interest.

Current research in the Sean T. Prigge Lab explores the biochemical pathways found in the apicoplast, an essential organelle found in malaria parasites, using a combination of cell biology and genetic, biophysical and biochemical techniques. We are particularly focused on the pathways used for the biosynthesis and modification of fatty acids and associated enzyme cofactors, including pantothenate, lipoic acid, biotin and iron-sulfur clusters. We want to better understand how the cofactors are acquired and used, and whether they are essential for the growth of blood-stage malaria parasites.

Dr. Sidhaye is interested in improving the care of persons with cystic fibrosis, type 1 diabetes mellitus and hospitalized person with diabetes. research topics include bone health of persons with CF undergoing lung transplant, CF-related diabetes mellitus, Care of persons with type 1 diabetes mellitus transitioning from pediatrics to adult specialty clinics, Management of hospitalized persons with diabetes.

The Jeremy Nathans Laboratory is focused on neural and vascular development, and the role of Frizzled receptors in mammalian development. We use gene manipulation in the mouse, cell culture models, and biochemical reconstitution to investigate the relevant molecular events underlying these processes, and to genetically mark and manipulate cells and tissues. Current experiments are aimed at defining additional Frizzled-regulated processes and elucidating the molecular mechanisms and cell biologic results of Frizzled signaling within these various contexts. Complementing these areas of biologic interest, we have ongoing technology development projects related to genetically manipulating and visualizing defined cell populations in the mouse, and quantitative analysis of mouse visual system function.