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Anastasia-Kralil

Anastasia Kralli

Research Interests

Organisms go through cycles of metabolic activity, driven by internal cues (circadian, circannual clocks) and physiologic/behavioral inputs (e.g. feeding/fasting, physical activity/rest). In addition, organisms face environmental challenges (physical, chemical or psychological stressors) that require continual adaptation of the pathways regulating metabolism. The goal of our research is to elucidate the regulatory and transcriptional mechanisms that integrate information and enable physiologic adaptations (particularly in response to changes in physical activity, environmental temperature, nutritional state), and that, when deregulated, contribute to metabolic disease.

Our studies focus on the Estrogen-Related Receptors (ERRα, ERRβ, and ERRγ), which we use as an entry point to the study of the regulatory / transcriptional networks that are important for adaptation in adipose tissue and in skeletal muscle, in response to changes in environmental temperature, physical exercise and/or diet. In past studies, we have shown that ERRs, and in particular ERRα, co-ordinate gene expression programs that regulate mitochondrial biogenesis and oxidative capacity. Our current studies build on this past work, using mouse models with genetically modified loci for ERRs (floxed alleles) and dissecting the unique and shared roles of ERRs in adipose tissue and in skeletal muscle. We are also identifying novel mechanisms that regulate ERR activity, as well as new important downstream effectors of ERRs, thereby expanding the network of regulators of mitochondrial oxidative function. Our studies identify and probe new avenues for therapeutic intervention in states where oxidative metabolism and tissue function are compromised, such as insulin resistance and type 2 diabetes, disease-associated muscle atrophies and age-related degenerative diseases.

William Guggino

William Guggino

Research Interests

Rapid movements of molecules across biological membranes are critical for many fundamental cells processes such as muscle contraction, neural conduction, and epithelial ion transport.  An understanding of the molecular biology of many of the transport proteins involved in these processes is beginning to emerge. It is also becoming clear that mutations in genes encoding proteins that alter membrane transport are associated with inherited disorders such as cystic fibrosis and polycystic kidney disease.  We use a combination of cell and molecular approaches to study the structure, function, regulation, development, and molecular biology of ion channels and the role of transport proteins in the disease process.  The following topics are currently being investigated:

  • Expression and structure/function studies of Cl- and water channels;
  • Identification of the specific defect in Cl- channel regulation in patients with Cystic Fibrosis, the most common autosomal recessive disease in North America;
  • Genetic therapies for the correction of defective ion transport in CF cells and patients.
  • Understanding the molecular defect in polycystic kidney disease a common autosomal dominant disorder.

Publications

Bibliography

Dax-Fu

Dax Fu

Research Interests

Zinc physiology with a focus on structure, function and regulation of zinc transporters.

Zinc transporters regulate subcellular zinc distributions to ensure proper metalation of numerous zinc enzymes and signaling molecules. Fluctuations of cytosolic zinc concentration constitute the basis for zinc signaling, but also challenge zinc homeostasis with broad disease implications. Our research is focusing on ZnT8, a pancreatic zinc transporter that mediates zinc enrichment in insulin secretory granules. ZnT8 is a major autoantigen in type-1 diabetes. A nonsynonymous variant of ZnT8 is also a validated risk factor contributing to the susceptibility of type-2 diabetes. We are investigating molecular mechanisms underlying the disease risk. Enabling technologies have been developed to study the structure and dynamic of ZnT8 at the molecular level, and its physiological roles in regulating insulin processing and secretion in beta cells. Research findings are being translated to new diagnostic tools and therapeutic interventions for early detection and treatments of diabetes.

Steven Claypool PhD, MA

Steven Claypool

Research Interests

Phospholipids are the building blocks of biological membranes which enable cells to separate biochemical pathways, establish specialized functions that can respond when appropriate, and adapt to constantly fluctuating metabolic conditions. My laboratory’s research focus is on the underappreciated contribution of the mitochondrion to cellular phospholipid metabolism. In addition to being the sole producer of the canonical mitochondrial lipid, cardiolipin (CL), the mitochondrion hosts one of the two major pathways in a cell for the production of phosphatidylethanolamine (PE). Ablation of the mitochondrial capacity to synthesize either CL or PE is embryonically lethal in mice. Moreover, in the yeast Saccharomyces cerevisiae, the combined absence of CL and PE is synthetically lethal. Using a combination of yeast and mammalian cell culture models, my lab currently has three major ongoing projects centered on different aspects of mitochondrial phospholipid metabolism in health and disease. The research objectives of our current projects are:

  1. To fill in the numerous structural and cell biological gaps in our understanding of the mitochondrial phosphatidylethanolamine biosynthetic pathway.
  2. To determine the physiological function(s) of TAZ-based CL remodeling.
  3. To understand how CL can influence the structure/function of a membrane protein, the ADP/ATP carrier, at a molecular level.

The long term goal of our basic research is to understand lipid assembly and remodeling pathways in the mitochondrion and relate deficits in these processes to human disease.

Publications

Bibliography

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