MANTP

Predoctoral Trainees

Megan Baumler (Groblewski Research Program): Diseases of the exocrine pancreas are major public health problems affecting tens of thousands of people annually.  I am interested in understanding the normal mechanism of secretion of digestive enzymes by the pancreas in order to ascertain how it is dysregulated in pathological states such as pancreatitis.  Specifically, I am investigating the roles of Cysteine String Protein (CSP) and Heat Shock Protein 70 (Hsp70) in the secretory pathway of pancreatic acinar cells in the physiologic and pathologic states.  CSP is a co-chaperone known to play a role in exocytosis of pancreatic enzymes such as amylase. However the specific role(s) of CSP in exocrine secretion by acinar cells is unclear.  Induction of Hsp70 prior to treatment of cells with supraphysiologic levels of cholecystokinin, which leads to the development of pancreatitis in rodents, is protective against the onset and severity of pancreatitis.  Our group found that atrophy of the pancreas induced by total parenteral nutrition (TPN) is associated with induction of Hsp70.  This finding has potential therapeutic implications given that in the clinical setting pancreatitis is often treated with TPN.  The mechanism of protection by Hsp70 has not been elucidated.  CSP is a cochaperone of Hsp70 and thus it is likely that together they play an essential role in the secretory pathway of acinar cells. Our main hypothesis is that CSP targets Hsp70 to the secretory pathway, and we would like to determine whether the conserved tripeptide sequence within the J-domain of CSP is necessary for the protective effects that Hsp70 offers against pancreatitis.  Further, we plan to clarify the mechanism behind the protective effects of Hsp70 that will offer insight into the pathophysiology of pancreatitis.

Jamie Cooper (Schoeller Research Program): Over one-third of adults in the U.S. are classified as obese.  Obesity results from a long-term failure of an individual to regulate energy intake to match energy expenditure.  Environmental correlates with obesity include high fat diets and a sedentary life style.  My research involves examining the effects of exercise and different high-fat diets on markers of hunger and satiety.  Research participants are placed on either a high mono-unsaturated or saturated fat diet, with and without exercise, for 5 days during which time we collect energy expenditure and fuel utilization data using a whole room indirect calorimeter.  To study the hormonal response to these diets and exercise, I will determine the twenty-four hour profile of the serum concentrations of leptin, insulin, ghrelin, and PYY along with subjective measures of hunger and satiety using a visual analog scale questionnaire.  Once these studies are concluded I will then test the hypothesis that altered regulation of secretion of satiety hormones contributes to the ability of gastric bypass surgery to promote weight loss.  I will examine the effect of gastric bypass surgery on the diet-induced changes in serum concentrations of these hormones by examining the single meal induced changes in hormone concentration before and after surgery.

Avery Frey (Eide Research Program): Zinc is an essential nutrient for all organisms because zinc-containing proteins are required for essential metabolic processes including many aspects of gene expression, defense against oxidative stress, and other key physiological processes.  Both zinc deficiency and zinc excess impair cell function.  Zinc deficiency is a significant global health problem impairing immunity, fertility and multiple other processes. Understanding how cells sense and respond to alterations in zinc status is key for elucidating the pathological impact of improper zinc nutriture.  We use yeast as a model system for defining the organismal
response to altered zinc availability. Zap1 is a transcriptional activator responsible for mediating zinc homeostasis in Saccharomyces cerevisiae through the transcriptional regulation of its target genes in response to zinc.  While most described activator proteins have a single activation domain, two have been mapped in Zap1, both of which are independently regulated by zinc.  Interestingly, both activation domains are conserved in Zap1 orthologues found in evolutionarily divergent species of yeast, suggesting that they each serve unique purposes in the function of Zap1.  My research focuses on elucidating the role of each activation domain of Zap1 and defining their individual contribution to target gene induction and zinc homeostasis.

Elizabeth McNeill (Clagett-Dame Research Program): Vitamin A deficiency is a major public health problem throughout the world.  Insufficient dietary intake of vitamin A is detrimental to the function of many organ systems in children and adults (e.g. vision, immunity) and vitamin A is also required for reproduction. The roles of vitamin A compounds, including retinoic acid, in early development include a critical function in brain development.  The Clagett-Dame lab discovered several retinoic acid genes induced in SH-SY5Y neuroblastoma cells including “retinoic acid induced in neuroblastoma 1” or RAINB1 (also known as neuron navigator 2 or NAV2). My research project involves characterizing and studying the function of NAV2 using both the nematode C. elegans and a mouse strain that is hypomorphic for NAV2. My work in C. elegans is focused on determining the role of putative protein domains of NAV2 in neurite outgrowth. The hypomorphic mouse model is being used in an effort to determine the role NAV2 plays in the development of the mammalian nervous system.

Postdoctoral Trainees

Matthew Flowers PhD (Ntambi Research Program): Obesity and its associated complications such as insulin resistance affect more than one-quarter of people in the U.S. The Ntambi lab has found that stearoyl-CoA desaturase 1 (SCD1), an enzyme critical for the generation of monounsaturated fatty acids, is a key factor controlling fat accumulation and influencing insulin sensitivity. My project is focused on elucidating the tissue-specific role of SCD1 in regulating obesity and insulin resistance. To accomplish this goal, I am using the Cre-loxP system to generate mice with a tissue-specific genomic deletion of the SCD1 gene in liver, fat, muscle, brain, and skin, and monitoring their susceptibility to both diet- and genetically-induced obesity. In addition to protection from obesity and insulin resistance, we have previously shown that mice with a whole-body deletion of SCD1 have several other metabolic changes such as decreased lipogenic gene expression, increased food intake, enhanced insulin sensitivity, cold intolerance, and skin abnormalities. Thus, I will monitor these phenotypes in the tissue-specific SCD1 knockouts as well to determine the physiologically relevant sites of monounsaturated fatty acid synthesis.

Matthew Koopmann MD (Ney Research Program): Adults suffering from ischemic or inflammatory bowel disease and infants with necrotizing enterocolitis are frequently treated surgically by massive intestinal resection.  Massive resection of the intestine without adequate intestinal adaptation reduces absorptive surface area leading to a complex of symptoms termed short bowel syndrome, a condition which affects approximately 30,000 people in the U.S. and often requires total parenteral nutrition for survival.  Intestinal adaptation following bowel resection is a poorly understood, neuroendocrine process that stimulates mucosal growth in the residual intestine.  The Ney laboratory investigates the hormonal, nutrient and other factors that influence intestinal adaptation.  They have previously shown that the intestinal growth factors glucagon-like peptide-2 (GLP-2) and insulin-like growth factor-I (IGF-I) are capable of stimulating mucosal growth facilitating intestinal adaptation in rats subjected to jejunoileal resection.  My goal is to test the hypothesis that intestinal adaptation is regulated by a neuroendocrine pathway which includes the vagus nerve, GLP-2 and IGF-I, a putative downstream mediator of GLP-2 action. My research will assess the role of GLP-2 action and its relevance to IGF-I expression in rodent models of massive intestinal resection.

Chad Paton PhD (Ntambi Research Program): My project focuses on understanding how fatty acid synthesis is dysregulated in cancer cells with the ultimate goal of determining how targeting specific genes in fatty acid synthesis might have pharmacological efficacy in cancer treatment.  De novo synthesis of fatty acids in peripheral tissues is generally a rare phenomenon, however in many tumors and cancer cell lines, Fatty Acid Synthase (FAS) and stearoyl CoA-desaturase (SCD) are highly up-regulated.  FAS generates saturated fatty acids that can be lipotoxic unless they are desaturated via SCD prior to their storage as triglycerides or conversion into phospholipids.  While it is known that inhibiting SCD activity in cancer cells can induce apoptosis, the mechanistic role of SCD in tumor progression is unknown.  It is expected that desaturation of intracellular lipids through SCD is a necessary event for the proliferation and survival of cancer cells. Therefore, preventing SCD activity will induce apoptosis by preventing the flux of lipids through signaling and membrane biosynthetic pathways and into neutral lipid storage compartments. My research goals fall into three areas, with the first to provide a mechanistic link between the proliferative effects of FAS overexpression using SCD-1 knockdown and overexpression strategies in the presence of exogenous fatty acids and FAS inhibition. Second, I am characterizing the expression patterns of Caveolin-1, SREBP-1c, SCAP, PGC1α and Insig-2a in several human breast and prostate cancer cell lines and MCF-10A control cells. I will also assess the distribution of various phospholipid species contained within lipid rafts as well as within the lipid disordered phase of the cell membrane.  These results will then be confirmed in tumor samples obtained from human patients in order to provide a more thorough and appropriate description of the phenotypic characteristics of FAS overexpressing, endogenous lipid dependent tumors and cells.  Finally, I will determine whether the PKB/Akt and Hedgehog signaling pathways are dependent on SCD expression in cancer cells.  The Hedgehog signaling proteins (Sonic, Indian, and Desert) are palmitoylated on their N- terminus and covalently coupled to cholesterol on their C-terminus.  The cellular receptors that mediate Hedgehog signaling contain sterol sensing domains and are localized within Caveolin-1 enriched lipid rafts.  These rafts serve as docking sites for several signaling pathways, including PKB/Akt, and it is likely that altering SCD activity can interfere with cholesterol biosynthesis to disrupt both raft assembly and signaling.  

Joel Walker PhD (Eide Research Program): Diseases caused by dietary or genetic deficiencies of zinc are a significant public health concern throughout the world.  Previous research in the Eide laboratory identified the ZnT and Zip families of zinc transporters and demonstrated that they are critical players in the regulation of eukaryotic zinc homeostasis.  My research project involves the characterization of the human zinc transporter Zip13, a ubiquitously expressed protein in human tissues.  I have shown that the Zip13 is a zinc-specific transporter when over-expressed in HeLa cells.  I have also focused on understanding how changes in cellular zinc status influence Zip13 expression.  In these studies I have found that zinc status controls Zip13 mRNA levels; Zip13 mRNA increase in zinc-limited cells.  More recently, I have used immunofluorescence microscopy and shown that endogenous Zip13 localizes to a vesicular compartment.  I am using currently using immunofluorescence and proteomics approaches to identify this compartment and in this manner elucidate the roles of Zip13 zinc transport in controlling cellular zinc homeostasis in vertebrates.