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- Title
- Deciphering the Role of Adrenergic Hormones in Embryonic Cardiac Calcium Signaling and Metabolism.
- Creator
-
Peoples, Jessica, Ebert, Steven, Davidson, Victor, Phanstiel, Otto, Yooseph, Shibu, University of Central Florida
- Abstract / Description
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The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are critical regulators of mammalian cardiovascular physiology. NE and EPI mediate stress responses to enhance cardiovascular function, however dysregulation of adrenergic signaling leads to heart failure, congenital heart malformations, and sudden cardiac death. Adrenergic hormone-expressing cells were found in the early embryonic heart, and NE has been determined essential for embryonic cardiac development. Despite extensive...
Show moreThe adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are critical regulators of mammalian cardiovascular physiology. NE and EPI mediate stress responses to enhance cardiovascular function, however dysregulation of adrenergic signaling leads to heart failure, congenital heart malformations, and sudden cardiac death. Adrenergic hormone-expressing cells were found in the early embryonic heart, and NE has been determined essential for embryonic cardiac development. Despite extensive work in adults, the regulatory roles and adrenergic targets of these hormones during embryonic cardiac development have not yet been fully determined. Prior transcriptomic studies from our lab showed that expression of signal transduction and metabolic genes in embryos lacking adrenergic hormones were by far the most affected categories of genes. Thus, we hypothesized that adrenergic hormones stimulate early calcium signaling, and are required for sufficient supply of energy substrates for the metabolic shift from anaerobic glycolysis to aerobic respiration during heart development. We utilized the dopamine ?-hydroxylase knock-out (Dbh-/-) mouse model to examine effects of adrenergic-deficiency on calcium signaling and metabolism during heart development. Using calcium-imaging and patch-clamp techniques, we found that calcium transients, voltage-gated calcium channels, and L-type calcium currents in adrenergic-deficient embryonic hearts were not affected relative to controls indicating adrenergic stimulation did not influence early calcium signaling. Metabolomics analyses of adrenergic-deficient hearts revealed disruption in glycolytic and pentose-phosphate pathways as well as reduced activity of respective regulatory enzymes, glyceraldehyde 3-phosphate dehydrogenase and glucose 6-phosphate dehydrogenase indicating compromised glucose metabolism. Addition of pyruvate to embryonic hearts led to significant recovery of ATP concentrations and oxygen consumption rates, thereby supporting the hypothesis that adrenergic-deficient hearts are (")starved(") of metabolic substrates required for transitions from anaerobic glycolysis to aerobic metabolism. Overall, we showed that adrenergic hormones are not necessary for calcium signaling in the embryonic heart, but are essential regulators ensuring sufficient metabolic substrate and boosting enzymatic activities to fuel aerobic metabolism.
Show less - Date Issued
- 2018
- Identifier
- CFE0007233, ucf:52223
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007233
- Title
- TESTING MICE AT RISK OF PANCREATIC CANCER FOR ALTERED PROTEIN PATHWAYS FOUND IN DIABETES.
- Creator
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Cheung, Henley, Altomare, Deborah A., University of Central Florida
- Abstract / Description
-
Pancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared...
Show morePancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared protein signaling pathways. In a previous study, hyper-activation of AKT1 resulted in a pre-diabetic phenotype and also increased upregulation of downstream phosphorylated mTOR and phosphorylated p70S6 kinase. More recently, mice with mutations that hyper-activated AKT1 and KRAS showed a significantly higher blood glucose level compared to littermate matched wild-type, mutant AKT1, or mutant KRAS mice. Interestingly, mice with a combination of mutations that hyper-activated AKT1 and KRAS also showed faster development of pancreatic cancer compared to these other groups of littermate mice. Toward determining a molecular basis for the crosstalk between AKT1 and KRAS, pancreas and liver tissues were collected from all four groups of mice including wild-type, mutant AKT1, mutant KRAS, and mice with dual AKT1/KRAS hyper-activation. One strategy was to examine expression and/or phosphorylation of downstream protein signaling crosstalk by analysis of p70S6K using Western Blots. Erk 1/2 proteins were also tested as downstream proteins of KRAS to provide a molecular view of the individual and cooperative roles of AKT1 and KRAS in the mouse models. A potential feedback mechanism to affect insulin receptor signaling in the pancreas was examined using enzyme-linked immunosorbent assays (ELISA). A significant decrease in insulin receptor phosphorylation, possibly contributing to insulin resistance, was found when mice had mutant hyper-activated KRAS. Contrary to the original expectations, mice with combined mutations of AKT1 and KRAS may contribute to the accentuated diabetic phenotype by targeting two different points in the AKT and KRAS protein signaling pathways. The information can help understand the relationship between glucose metabolism, diabetes, and pancreatic cancer development. By thoroughly studying the interactions between targets in the AKT1/KRAS signaling pathways, key molecular events that induce metabolic changes and potentially early biomarkers may lead to an improved understanding of risk and/or detection of pancreatic cancer.
Show less - Date Issued
- 2017
- Identifier
- CFH2000273, ucf:45895
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000273