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Jennifer Pluznick PhD

Jennifer Pluznick

Research Interests

Elucidating the role of sensory receptors (olfactory receptors and other sensory GPCRs) in regulating renal and cardiovascular function; elucidating the role of the gut microbiota in renal and cardiovascular function

Our lab is interested in the role that chemosensation plays in regulating physiological processes, particularly in the kidney and the cardiovascular system. We have found that sensory receptors (olfactory receptors, taste receptors, and other G-protein coupled receptors) are expressed in the kidney and in blood vessels, and that individual receptors play functional roles in whole-animal physiology.  We are working to understand the role that each receptor plays in whole-animal physiology by using a variety of in vitro (receptor localization, ligand screening) and in vivo (whole-animal physiology) techniques.  We have found that two renal/cardiovascular sensory receptors modulate blood pressure regulation in response to changes in gut microbial metabolites; thus, we also exploring the interplay of sensory receptors, the gut microbiota, and blood pressure regulation.

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Svetlana Lutsenko PhD

Svetlana Lutsenko

Research Interests

Copper homeostasis: mechanism of transport, protein and metabolic networks, integrative approaches to human disease

Copper plays an essential role in human physiology. It is an essential cofactor of enzymes that are required for respiration, biosynthesis of neurotransmitter, detoxification of radicals, blood clotting, connective tissue formation, and many others processes. Recent data suggest that coppers serves as a signaling molecules and regulates myelination of neurons, inflammatory response, and angiogenesis. Copper also alters the sensitivity of cancer cells to chemotherapeutic drugs, such as cisplatin.  The long-term goal of our research is provide a detailed understanding of human copper homeostasis in health and disease.

Structure, Function, and Regulation of Human Copper Transporters

In human cells, copper levels are controlled by two copper-transporting ATPases, ATP7A and ATP7B. Genetic mutations in ATP7A result in a systemic copper deficiency, particularly in the CNS, and Menkes disease. Menkes disease has a profound effect on human growth and development, and is mostly fatal. Mutations in another copper transporter, ATP7B, are associated with copper accumulation in tissues, particularly in the liver, and Wilson disease. Wilson disease affects primarily children and young adults and has hepatic, neurologic and psychiatric manifestations.

Our group studies the function and regulation of ATP7A and ATP7B in different cell types. We use a combination of biochemical, biophysical, and cell biological approaches to understand the mechanism of copper transport and effects of mutations on the structure and activity of copper transporters. The intracellular localization of ATP7A and ATP7B is regulated by changes in copper levels and hormones. By using site-directed mutagenesis and regulated expression of copper transporters in mammalian cells, we investigate how ATP7A and ATP7B sense changing copper levels and adjust their intracellular location and activity. Through a collaborative whole-genome screening we identified novel regulators of copper homeostasis and we are investigating their role in activity, stability, and trafficking of copper transporters.

Copper chaperones

The intracellular concentration of free copper is tightly controlled. In a cytosol, copper is carried around by small shuttle proteins called copper chaperones or metallochaperones. These proteins distribute copper to different cellular destinations (cytosol, mitochondria, secretory pathway) and modulate activity of their target enzymes. We have discovered that the copper-chaperone Atox1 is a redox sensitive molecule that serves as an important switch directing more copper towards the secretory pathway during neuronal differentiation.  We have developed a mouse model for targeted deletion of Atox1 and plan to better understand the role of Atox1 in copper metabolism in the brain

Molecular Mechanisms of Wilson disease

Copper misbalance has severe consequences for cell physiology. We are using the genetically engineered mice with a global and tissue specific deletions of ATP7B to better understand (i) the molecular and cellular events that trigger the onset of pathology in different tissues, (ii) the mechanism of disease progression, and (iii) the role of various metabolic pathways in specific disease manifestations. Our goal is to generate a comprehensive and predictive model for Wilson disease. To achieve this goal, we investigate the copper-induced changes at a single cell level and combine these studies with a large-scale analysis of a proteome, metallome and transcriptomes. We have identified lipid metabolism and liver nuclear receptors as important players in disease pathogenesis and are developing new therapeutic approaches for Wilson disease

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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.

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