Sherry, A. Dean
Permanent URI for this collectionhttps://hdl.handle.net/10735.1/3917
Dean Sherry is a Professor of Chemistry and holds the Cecil H. and Ida Green Distinguished Chair in Systems Biology. He holds a joint appointment as Professor of Radiology at UT Southwestern Medical Center where he also serves as director of the Advanced Imaging Research Center. His research interests involve "the design of novel MR imaging agents that are responsive to physiology and metabolism." Learn more about Professor Sherry on his Faculty profile, Endowed Professorships and Chairs, UT Southwestern Faculty Profile, Sherry Lab and Research Explorer pages.
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Item In Vivo Assessment of Increased Oxidation of Branched-Chain Amino Acids in Glioblastoma(Nature Publishing Group, 2019-01-23) Suh, Eul Hyun; Hackett, Edward P.; Wynn, R. Max; Chuang, David T.; Zhang, Bo; Luo, Weibo; Sherry, A. Dean; Park, Jae Mo; 0000-0002-7404-6971 (Park, JM); 0000-0001-7150-8301 (Sherry, AD); Sherry, A. Dean; Park, Jae MoAltered branched-chain amino acids (BCAAs) metabolism is a distinctive feature of various cancers and plays an important role in sustaining tumor proliferation and aggressiveness. Despite the therapeutic and diagnostic potentials, the role of BCAA metabolism in cancer and the activities of associated enzymes remain unclear. Due to its pivotal role in BCAA metabolism and rapid cellular transport, hyperpolarized ¹³C-labeled α-ketoisocaproate (KIC), the α-keto acid corresponding to leucine, can assess both BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase complex (BCKDC) activities via production of [1-¹³C]leucine or ¹³CO₂ (and thus (H¹³CO₃-), respectively. Here, we investigated BCAA metabolism of F98 rat glioma model in vivo using hyperpolarized ¹³C-KIC. In tumor regions, we observed a decrease in ¹³C-leucine production from injected hyperpolarized ¹³C-KIC via BCAT compared to the contralateral normal-appearing brain, and an increase in H¹³CO₃-, a catabolic product of KIC through the mitochondrial BCKDC. A parallel ex vivo ¹³C NMR isotopomer analysis following steady-state infusion of [U-¹³C] leucine to glioma-bearing rats verified the increased oxidation of leucine in glioma tissue. Both the in vivo hyperpolarized KIC imaging and the leucine infusion study indicate that KIC catabolism is upregulated through BCAT/BCKDC and further oxidized via the citric acid cycle in F98 glioma.Item A Novel Inhibitor of Pyruvate Dehydrogenase Kinase Stimulates Myocardial Carbohydrate Oxidation in Diet-Induced Obesity(American Society for Biochemistry and Molecular Biology Inc.) Wu, C. -Y; Satapati, S.; Gui, W.; Max Wynn, R.; Sharma, G.; Lou, M.; Qi, X.; Burgess, S. C.; Malloy, C.; Khemtong, C.; Sherry, A. Dean; Chuang, D. T.; Merritt, M. E.; Sherry, A. DeanThe pyruvate dehydrogenase complex (PDC) is a key control point of energy metabolism and is subject to regulation by multiple mechanisms, including posttranslational phosphorylation by pyruvate dehydrogenase kinase (PDK). Pharmacological modulation of PDC activity could provide a new treatment for diabetic cardiomyopathy, as dysregulated substrate selection is concomitant with decreased heart function. Dichloroacetate (DCA), a classic PDK inhibitor, has been used to treat diabetic cardiomyopathy, but the lack of specificity and side effects of DCA indicate a more specific inhibitor of PDK is needed. This study was designed to determine the effects of a novel and highly selective PDK inhibitor, 2((2,4-dihydroxyphenyl)sulfonyl) isoindoline-4,6-diol (designated PS10), on pyruvate oxidation in diet-induced obese (DIO) mouse hearts compared with DCA-treated hearts. Four groups of mice were studied: lean control, DIO, DIO + DCA, and DIO + PS10. Both DCA and PS10 improved glucose tolerance in the intact animal. Pyruvate metabolism was studied in perfused hearts supplied with physiological mixtures of long chain fatty acids, lactate, and pyruvate. Analysis was performed using conventional ¹H and ¹³C isotopomer methods in combination with hyperpolarized [1-¹³C]pyruvate in the same hearts. PS10 and DCA both stimulated flux through PDC as measured by the appearance of hyperpolarized [¹³C]bicarbonate. DCA but not PS10 increased hyperpolarized [1-¹³C]lactate production. Total carbohydrate oxidation was reduced in DIO mouse hearts but increased by DCA and PS10, the latter doing so without increasing lactate production. The present results suggest that PS10 is a more suitable PDK inhibitor for treatment of diabetic cardiomyopathy.Item Influence of Dy³⁺ and Tb³⁺ Doping on ¹³C Dynamic Nuclear Polarization(American Institute of Physics Inc, 2017-01-03) Niedbalski, Peter; Parish, Christopher; Kiswandhi, Andhika; Fidelino, L.; Khemtong, C.; Hayati, Z.; Song, L.; Martins, Andr©; Sherry, A. Dean; Lumata, Lloyd L.; Niedbalski, Peter; Parish, Christopher; Kiswandhi, Andhika; Martins, Andr©; Sherry, A. Dean; Lumata, LloydDynamic nuclear polarization (DNP) is a technique that uses a microwave-driven transfer of high spin alignment from electrons to nuclear spins. This is most effective at low temperature and high magnetic field, and with the invention of the dissolution method, the amplified nuclear magnetic resonance (NMR) signals in the frozen state in DNP can be harnessed in the liquid-state at physiologically acceptable temperature for in vitro and in vivo metabolic studies. A current optimization practice in dissolution DNP is to dope the sample with trace amounts of lanthanides such as Gd3+ or Ho3+, which further improves the polarization. While Gd³⁺ and Ho³⁺ have been optimized for use in dissolution DNP, other lanthanides have not been exhaustively studied for use in ¹³C DNP applications. In this work, two additional lanthanides with relatively high magnetic moments, Dy³⁺ and Tb³⁺, were extensively optimized and tested as doping additives for ¹³C DNP at 3.35 T and 1.2 K. We have found that both of these lanthanides are also beneficial additives, to a varying degree, for ¹³C DNP. The optimal concentrations of Dy³⁺ (1.5 mM) and Tb³⁺ (0.25 mM) for ¹³C DNP were found to be less than that of Gd³⁺ (2 mM). W-band electron paramagnetic resonance shows that these enhancements due to Dy³⁺ and Tb³⁺ doping are accompanied by shortening of electron T₁ of trityl OX063 free radical. Furthermore, when dissolution was employed, Tb³⁺-doped samples were found to have similar liquid-state ¹³C NMR signal enhancements compared to samples doped with Gd³⁺, and both Tb³⁺ and Dy³⁺ had a negligible liquid-state nuclear T₁ shortening effect which contrasts with the significant reduction in T₁ when using Gd³⁺. Our results show that Dy³⁺ doping and Tb³⁺ doping have a beneficial impact on ¹³C DNP both in the solid and liquid states, and that Tb³⁺ in particular could be used as a potential alternative to Gd³⁺ in ¹³C dissolution DNP experiments.Item A Novel Class of Polymeric pH-Responsive MRI CEST Agents(2013-05-26) Zhang, Shanrong; Zhou, K.; Huang, G.; Takahashi, Masaya; Sherry, A. Dean; Gao, Jinming; Sherry, A. DeanIn this communication, we report that ionizable, tertiary amine-based block copolymers can be used as pH-responsive contrast agents for magnetic resonance imaging (MRI) through the chemical exchange saturation transfer (CEST) mechanism. The CEST signal is essentially "off" when the polymers form micelles near physiological pH but is activated to the "on" state when the micelles dissociate in an acidic environment.Item A Europium(Ⅲ)-Based PARACEST Agent for Sensing Singlet Oxygen by MRI(2013-04-04) Song, Bo; Wu, Yunkou; Yu, Mengxiao; Zhao, Piyu; Zhou, Chen; Kiefer, Garry E.; Sherry, A. Dean; Sherry, A. DeanA europium(Ⅲ) DOTA-tetraamide complex was designed as a MRI sensor of singlet oxygen (¹O₂). The water soluble, thermodynamically stable complex reacts rapidly with ¹O₂ to form an endoperoxide derivative that results in an ~3 ppm shift in the position of the Eu(Ⅲ)-bound water chemical exchange saturation transfer (CEST) peak. The potential of using this probe to detect accumulation of the endoperoxide derivative in biological media by ratiometric CEST imaging was demonstrated.;