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 Cardio Training Grant | Postdoctoral Fellowships | Current Fellows

Current Postdoctoral Fellows

Olga Chernysh,Ph.D.         
Mentor: Donald R.Menick,Ph.D.,Department of Medicine,Division of Cardiology

Olga received  herPhDin Biomedical Sciences from the University of Medicine and Dentistry of New Jersey in 2008 (mentor Dr. John P. Reeves). In her PhD dissertation research, Olga studied regulation of the cardiac sodium/calcium exchanger (NCX1) by cytosolic calcium and sodium. She was recruited into the cardiovascular training program supported by this T32 grant in 2009. The focus of her current research project is the regulation of NCX1 expression in cardiac myocytes. It is known that NCX1 is regulated at the transcriptional level in cardiac hypertrophy and heart failure. Changes in the expression levels of sodium/calcium exchanger can affect sarcoplasmic reticulum calcium loading and directly contribute to contractile dysfunction of failing myocardium. In animal models, it has been demonstrated that pharmacological inhibition of NCX1 may be beneficial in heart failure and during ischemia/reperfusion. Most studies, however, have focused only on the acute effects of NCX1 inhibitors on calcium homeostasis, and there is little information available on the potential risks and benefits of chronic therapeutic inhibition of NCX1. It has been shown that prolonged treatment with NCX1 inhibitor, KB-R7943 results in the upregulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. This upregulation is mediated via the activation of p38 and formation of a NCX1-p38 complex. However, the signaling pathways leading to the increase in Ncx1 gene expression remain to be elucidated. The goal of Olga’s project is to identify the components of the NCX1 macromolecular complex and the signaling pathways that may play a role in regulating Ncx1 gene expression in response to pharmacological inhibition of the exchanger.

Trainee Travel Grant Award, Heart Failure Society of America, 2010

Shaina Eckhouse, M.D.          
Mentor: John Ikonomides, M.D., and Jeffrey Jones, Ph.D., Department of Surgery, Division of Cardiothoracic Surgery
University of South Carolina. From June 2010 to present, Shaina is a current NIH T32 Postdoctoral Fellow on the grant. Her current research focuses on the role of matrix metalloproteinases (MMPs) during myocardial ischemia-reperfusion. Coronary revascularization and acute coronary syndromes are accompanied by myocardial ischemia-reperfusion (I/R), which can result in reduced regional contractility, likely due to both cellular and extracellular events. A unique transmembrane protease, the membrane type-1 matrix metalloproteinase (MT1-MMP), is induced in patients with I/R, but the interrelationship between downstream MT1-MMP proteolytic events and myocardial function with I/R remains unknown. Based upon in silico mapping, a potential MT1-MMP substrate is latent transforming growth factor binding protein (LTBP-1), which would
enhance release of the profibrotic transforming growth factor (TGF-β). A newly discovered class of post-transcriptional regulatory molecules is the microRNAs (miRs), but the relationship of specific miRs to MT1-MMP induction with I/R remains unknown. Accordingly, using a relevant pig model of I/R and a novel in vivo microdialysis approach to measure interstitial MT1-MMP activity and LTBP-1 hydrolysis, Shaina’s study tested the hypothesis that I/R causes differential MT1-MMP substrate processing and would be associated with the interstitial release of MT1-MMP specific regulatory miR. Target mapping revealed that the miR-133a has a high sequence concordance for MT1-MMP. Thus, high sensitivity interstitial measurements of miR-133a were performed at identical time points. While segmental shortening, MT1-MMP activity, LTBP-1 proteolysis and miR-133a levels were identical at baseline between the I/R and remote regions, changes were observed at peak ischemia and following reperfusion. Within the I/R region, segmental shortening fell, MT1-MMP specific LTBP-1 hydrolysis increased, and interstitial miR-133a decreased. With reperfusion in the I/R region, segmental shortening remained decreased (consistent with myocardial stunning) and MT1-MMP activity increased. In contrast in the remote region, segmental shortening, MT1-MMP activity or LTBP-1 hydrolysis were unaffected at peak ischemia, but interstitial miR-133a levels fell. At reperfusion in the remote region, a robust increase in MT1-MMP activity occurred with a persistent reduction in interstitial miR-133a levels. MT1-MMP processed a critical factor in TGF- mediated signaling (LTBP-1) within the I/R region with peak ischemia, whereas the opposite occurred within the remote region. Thus, while I/R induced MT1-MMP within the entire myocardium, the downstream proteolytic targets are region- and time-specific. Next, this study demonstrated dynamic changes in interstitial miR release occur with I/R, whereby a specific MT1-MMP inhibitory miR (miR-133a) fell in a time- and region-specific manner. Since reduced miR-133a with I/R would enhance post-transcriptional induction of MT1-MMP, modulating myocardial miR-133a may be a potential upstream target by which to regulate MT1-MMP induction. These unique results provide new insight and potential therapeutic targets with respect to I/R mediated contractile dysfunction.

National ScienceFoundation, MRI: Acquisition of Centrifugation, Refrigeration and Sterilizing Equipment to Enhance the Research Program for Faculty and Undergraduate Students at FMU, 2009
NCRR P20 RR016461, INBRE Grant, FMU Biomedical Research Enhancement Program, 09/12/10-06/30/15

Jay Stallons, Ph.D.
Mentor: Rick Schnellmann, Ph.D., College of Pharmacy, Pharmaceutical and Biomedical Sciences
Jay received his PhD in May 2011 from the University of Louisville in Pharmacology & Toxicology.
His research focuses on urinary mitochondrial DNA as a novel biomarker of acute kidney injury.
Acute kidney injury (AKI) is defined by the abrupt reduction in kidney function and can be caused by numerous acute insults including drug toxicity, surgery, trauma, and ischemia/reperfusion (I/R). Animal models of AKI have demonstrated an important role for mitochondrial dysfunction, and mitochondrial components are released from cells and tissues after diverse insults to act as damage-associated molecular patterns (DAMPs) in signaling injury responses. Serum creatinine (SCr) is the standard clinical marker for AKI, but the limited sensitivity of SCr has led to recent efforts by multiple groups to identify novel biomarkers of AKI. The purpose of this study was to determine if urinary mitochondrial DNA (mtDNA) is a biomarker of AKI and of mitochondrial dysfunction in AKI. We established a rat model of renal I/R in which SCr increased from 0.5 to 2.2 mg/dl at 24 hr after surgery and returned to normal levels after 144 hr. We collected urine from sham and I/R rats at 24 hr and concentrated 1 ml of urine using centrifugal filters. DNA was isolated from concentrated urine, qPCR was performed using primers for the mitochondrial gene ND1, and ND1 was quantified using a standard curve of kidney DNA. There was a 184-fold increase in the levels of ND1 in urine from I/R rats compared to sham animals. We also examined mtDNA quantity in the urine of humans with AKI after cardiac surgery, control humans with normal renal function, and humans with no AKI after cardiac surgery. We found a 100-fold increase in urinary ND1 from humans with AKI versus healthy controls and cardiac surgery patients with no AKI. Our results indicate that urinary mtDNA may be a novel, noninvasive biomarker of AKI and could be indicative of mitochondrial dysfunction in renal toxicity.

Kamala Sundararaj, Ph.D.
Mentor: Dhan Kuppuswamy, Ph.D., Department of Medicine, Division of Cardiology
Kamala received her PhD in Biochemistry from the Vinayaka Missions University in India in 2011.
One mechanism hypothesized to contribute to insulin resistance and the complications associated with diabetes is the altered regulation of O-GlcNAc transferase (OGT) and O-GlcNAcase(OGA). These enzymes are responsible for the addition and removal of N-acetylglucosamine (O-GlcNAc) to protein Ser/Thr residues. To understand the molecular mechanisms in the pathophysiologic status of diet induced obese and diabetic animals, we examined C57BL/6 male mice that were fed with two kinds of diets for 12 to 16 weeks; a normal chow diet (NCD), a high fat diet (HFD). The liver specific knock out of IRS-1/2 mice were also fed with NCD and HFD. The mRNA and protein expression levels of OGT, OGA, GCK, PCK, G6P, IRS-1 and IRS-2 in liver tissues from the two groups were measured. In the present study, we have found that the hepatic expression of OGT in NCD and HFD mice are increased with feeding. We also observed decreased hepatic OGT expression in HFD mice compared with the NCD mice in both fasted and fed state. Moreover, we found that the level of hepatic OGT expression was further decreased in HFD mice with the liver specific knock out (KO) of IRS-1/2. Conversely, the hepatic OGA expression was opposite to that of OGT. Interestingly, in HFD mice the hepatic O-GlcNAc modification was increased in both fasted and fed condition compared with the NCD mice. This increase was further augmented in liver specific IRS-1/2 KO HFD mice compared with the NCD IRS-1/2 KO mice. In conclusion, these studies show for the first time that IRS-1/2 mediated insulin signaling is essential for hepatic OGT and OGA expression also OGT decrease in HFD IRS1/2 KO mice may play a protective role.



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