Research

Molecular Medicine

Research within the Division of Molecular Medicine is dedicated to defining the metabolic determinants of chronic diseases. Genetically modified animal models and studies in human subjects are combined with sophisticated isotopic tracing, computational flux modeling, and metabolomics approaches to allow our research to fully encompass the complexities of integrated physiology in health and disease. Our researchers aim to leverage the knowledge acquired from our experimental investigations to prevent, identify, and treat metabolic diseases including insulin resistance, nonalcoholic fatty liver disease, liver cancer, and cardiovascular disease. 

PUBLICATIONS

Crawford and Puchalska Lab

2020

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.
Zhang Y, Taufalele PV, Cochran JD, Robillard-Frayne I, Marx JM, Soto J, Rauckhorst AJ, Tayyari F, Pewa AD, Gray LR, Teesch LM, Puchalska P, Funari TR, McGlauflin R, Zimmerman K, Kutschke WJ, Cassier T, Hitchcock S, Lin K, Kato KM, Stueve JL, Haff L, Weiss RM, Cox JE, Rutter J, Taylor EB, Crawford PA, Lewandowski ED, Des Rosiers C, Abel ED.
Nat Metab. 2020 Oct 26. doi: 10.1038/s42255-020-00288-1. PMID: 33106689 0

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation.
Al Batran R, Gopal K, Capozzi ME, Chahade JJ, Saleme B, Tabatabaei-Dakhili SA, Greenwell AA, Niu J, Almutairi M, Byrne NJ, Masson G, Kim R, Eaton F, Mulvihill EE, Garneau L, Masters AR, Desta Z, Velázquez-Martínez CA, Aguer C, Crawford PA, Sutendra G, Campbell JE, Dyck JRB, Ussher JR.
Cell Metab. 2020 May 5;31(5):909-919.e8. doi: 10.1016/j.cmet.2020.03.017. Epub 2020 Apr 9. PMID: 32275862

Nonalcoholic Steatohepatitis: A Review.
Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S.
JAMA. 2020 Mar 24;323(12):1175-1183. doi: 10.1001/jama.2020.2298. PMID: 32207804.

2019

Ketogenic therapies for lymphedema?
Puchalska P, Crawford PA.
Nat Metab. 2019 Jul;1(7):656-657. doi: 10.1038/s42255-019-0090-3.PMID: 32694645. 

Pyruvate Carboxylase Wields a Double-Edged Metabolic Sword.
Hughey CC, Crawford PA.
Cell Metab. 2019 Jun 4;29(6):1236-1238. doi: 10.1016/j.cmet.2019.05.013.PMID: 31167118. 

Application of Stable Isotope Labels for Metabolomics in Studies in Fatty Liver Disease.
Puchalska P, Crawford PA.
Methods Mol Biol. 2019; 1996:259-272. doi: 10.1007/978-1-4939-9488-5_20.PMID: 31127561 

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense.
Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, Petucci C, Lewandowski ED, Crawford PA, Muoio DM, Recchia FA, Kelly DP
JCI Insight. 2019 Feb 21;4(4):e124079. doi: 10.1172/jci.insight.124079. eCollection 2019 Feb 21.PMID: 30668551. 

Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis.
Puchalska P, Martin SE, Huang X, Lengfeld JE, Daniel B, Graham MJ, Han X, Nagy L, Patti GJ, Crawford PA.
Cell Metab. 2019 Feb 5;29(2):383-398.e7. doi: 10.1016/j.cmet.2018.10.015. Epub 2018 Nov 15.PMID: 30449686.

2018

Transport-exclusion pharmacology to localize lactate dehydrogenase activity within cells.
Niu X, Chen YJ, Crawford PA, Patti GJ.
Cancer Metab. 2018 Dec 12;6:19. doi: 10.1186/s40170-018-0192-5. eCollection 2018.PMID: 30559963 

Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure.
Wang C, Liu F, Frisch-Daiello JL, Martin S, Patterson TA, Gu Q, Liu S, Paule MG, Hanig JP, Slikker W Jr, Crawford PA, Wang C, Han X.
Anal Chim Acta. 2018 Dec 11;1037:87-96. doi: 10.1016/j.aca.2017.11.052. Epub 2017 Nov 30.PMID: 30292318. 

Isotope Tracing Untargeted Metabolomics Reveals Macrophage Polarization-State-Specific Metabolic Coordination across Intracellular Compartments.
Puchalska P, Huang X, Martin SE, Han X, Patti GJ, Crawford PA.
iScience. 2018 Nov 30;9:298-313. doi: 10.1016/j.isci.2018.10.029. Epub 2018 Nov 2.PMID: 30448730. 

Refueling the Failing Heart: A Case for Sodium-Glucose Cotransporter 2 Inhibition in Cardiac Energy Homeostasis.
Crawford PA.
JACC Basic Transl Sci. 2018 Aug 26;3(5):588-590. doi: 10.1016/j.jacbts.2018.08.002. eCollection 2018 Oct.PMID: 30456330.

Ketone bodies as epigenetic modifiers.
Ruan HB, Crawford PA.
Curr Opin Clin Nutr Metab Care. 2018 Jul;21(4):260-266. doi: 0.1097/MCO.0000000000000475.PMID: 29697540. 

Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome.
d'Avignon DA, Puchalska P, Ercal B, Chang Y, Martin SE, Graham MJ, Patti GJ, Han X, Crawford PA.
JCI Insight. 2018 Jun 21;3(12):e99762. doi: 10.1172/jci.insight.99762. eCollection 2018 Jun 21.PMID: 29925686. 

Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin.
Polidori D, Iijima H, Goda M, Maruyama N, Inagaki N, Crawford PA.
Diabetes Obes Metab. 2018 May;20(5):1321-1326. doi: 10.1111/dom.13224. Epub 2018 Feb 14.PMID: 29341404.

2017

Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond.
Ruiz M, Labarthe F, Fortier A, Bouchard B, Thompson Legault J, Bolduc V, Rigal O, Chen J, Ducharme A, Crawford PA, Tardif JC, Des Rosiers C.
Am J Physiol Heart Circ Physiol. 2017 Oct 1;313(4):H768-H781. doi: 10.1152/ajpheart.00820.2016. Epub 2017 Jul 14.PMID: 28710072

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics.
Puchalska P, Crawford PA.
Cell Metab. 2017 Feb 7;25(2):262-284. doi: 10.1016/j.cmet.2016.12.022.PMID: 28178565. 

2016

Comprehensive and Quantitative Analysis of Polyphosphoinositide Species by Shotgun Lipidomics Revealed Their Alterations in db/db Mouse Brain.
Wang C, Palavicini JP, Wang M, Chen L, Yang K, Crawford PA, Han X.
Anal Chem. 2016 Dec 20;88(24):12137-12144. doi: 10.1021/acs.analchem.6b02947. Epub 2016 Dec 1.PMID: 28193056

Lactate metabolism is associated with mammalian mitochondria.
Chen YJ, Mahieu NG, Huang X, Singh M, Crawford PA, Johnson SL, Gross RW, Schaefer J, Patti GJ.
Nat Chem Biol. 2016 Nov;12(11):937-943. doi: 10.1038/nchembio.2172. Epub 2016 Sep 12.PMID: 27618187.

The Failing Heart Relies on Ketone Bodies as a Fuel.
Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Krüger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP.
Circulation. 2016 Feb 23;133(8):698-705. doi: 10.1161/CIRCULATIONAHA.115.017355. Epub 2016 Jan 27.PMID: 26819376.

2015

The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD.
Nat Med. 2015 Mar;21(3):263-9. doi: 10.1038/nm.3804. Epub 2015 Feb 16.PMID: 25686106.

2014

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.
Potter DG, Ercal B, Huang X, Leid JM, d'Avignon DA, Graham MJ, Dietzen DJ, Brunt EM, Patti GJ, Crawford PA.
Clin Invest. 2014 Dec;124(12):5175-90. doi: 10.1172/JCI76388. Epub 2014 Oct 27.PMID: 25347470.

Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling.
Schugar RC, Moll AR, André d'Avignon D, Weinheimer CJ, Kovacs A, Crawford PA.
Mol Metab. 2014 Aug 13;3(7):754-69. doi: 10.1016/j.molmet.2014.07.010. eCollection 2014 Oct.PMID: 25353003.

Impairments of hepatic gluconeogenesis and ketogenesis in PPARα-deficient neonatal mice.
Cotter DG, Ercal B, d'Avignon DA, Dietzen DJ, Crawford PA.
Am J Physiol Endocrinol Metab. 2014 Jul 15;307(2):E176-85. doi: 10.1152/ajpendo.00087.2014. Epub 2014 May 27.PMID: 24865983.U

X13CMS: global tracking of isotopic labels in untargeted metabolomics.
Huang X, Chen YJ, Cho K, Nikolskiy I, Crawford PA, Patti GJ.
Anal Chem. 2014 Feb 4;86(3):1632-9. doi: 10.1021/ac403384n. Epub 2014 Jan 24.PMID: 24397582.

 2013

Role of choline deficiency in the Fatty liver phenotype of mice fed a low protein, very low carbohydrate ketogenic diet.
Schugar RC, Huang X, Moll AR, Brunt EM, Crawford PA.
PLoS One. 2013 Aug 29;8(8):e74806. doi: 10.1371/journal.pone.0074806. eCollection 2013.PMID: 24009777.

Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth.
Cotter DG, Ercal B, d'Avignon DA, Dietzen DJ, Crawford PA.
J Biol Chem. 2013 Jul 5;288(27):19739-49. doi: 10.1074/jbc.M113.454868. Epub 2013 May 20.PMID: 23689508. 

PGC-1β and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner.
Chambers KT, Chen Z, Lai L, Leone TC, Towle HC, Kralli A, Crawford PA, Finck BN.
Mol Metab. 2013 May 9;2(3):194-204. doi: 10.1016/j.molmet.2013.05.001. eCollection 2013.PMID: 24049734.

Ketone body metabolism and cardiovascular disease.
Cotter DG, Schugar RC, Crawford PA.
Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1060-76. doi: 10.1152/ajpheart.00646.2012. Epub 2013 Feb 8.PMID: 23396451. 

Metabolic stress in the myocardium: adaptations of gene expression.
Crawford PA, Schaffer JE.
J Mol Cell Cardiol. 2013 Feb;55:130-8. doi: 10.1016/j.yjmcc.2012.06.008. Epub 2012 Jun 21.PMID: 22728216.

Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation.
Cotter DG, Schugar RC, Wentz AE, d'Avignon DA, Crawford PA.
Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E363-74. doi: 10.1152/ajpendo.00547.2012. Epub 2012 Dec 11.PMID: 23233542.

2012

Liver-specific PGC-1beta deficiency leads to impaired mitochondrial function and lipogenic response to fasting-refeeding.
Chambers KT, Chen Z, Crawford PA, Fu X, Burgess SC, Lai L, Leone TC, Kelly DP, Finck BN.
PLoS One. 2012;7(12):e52645. doi: 10.1371/journal.pone.0052645. Epub 2012 Dec 28.PMID: 23285128.

Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease.
Schugar RC, Crawford PA.
Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):374-80. doi: 10.1097/MCO.0b013e3283547157.PMID: 22617564.

2011

Altered systemic ketone body metabolism in advanced heart failure.
Janardhan A, Chen J, Crawford PA.
Tex Heart Inst J. 2011;38(5):533-8.PMID: 22163128. 

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.
Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA.
Am J Physiol Gastrointest Liver Physiol. 2011 Jun;300(6):G956-67. doi: 10.1152/ajpgi.00539.2010. Epub 2011 Mar 31.PMID: 21454445.

Obligate role for ketone body oxidation in neonatal metabolic homeostasis.
Cotter DG, d'Avignon DA, Wentz AE, Weber ML, Crawford PA.
J Biol Chem. 2011 Mar 4;286(9):6902-10. doi: 10.1074/jbc.M110.192369. Epub 2011 Jan 5.PMID: 21209089.

2010

Akt2 deficiency promotes cardiac induction of Rab4a and myocardial β-adrenergic hypersensitivity.
Etzion S, Etzion Y, DeBosch B, Crawford PA, Muslin AJ.
J Mol Cell Cardiol. 2010 Dec;49(6):931-40. doi: 10.1016/j.yjmcc.2010.08.011. Epub 2010 Aug 20.PMID: 20728450.

Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.
Wentz AE, d'Avignon DA, Weber ML, Cotter DG, Doherty JM, Kerns R, Nagarajan R, Reddy N, Sambandam N, Crawford PA.
J Biol Chem. 2010 Aug 6;285(32):24447-56. doi: 10.1074/jbc.M110.100651. Epub 2010 Jun 7.PMID: 20529848. 

Epitope mapping in cell surface proteins by site-directed masking: defining the structural elements of NTPDase3 inhibition by a monoclonal antibody.
Ivanenkov VV, Crawford PA, Toyama A, Sévigny J, Kirley TL.
Protein Eng Des Sel. 2010 Jul;23(7):579-88. doi: 10.1093/protein/gzq027. Epub 2010 May 27.PMID: 20511214. 

Coordinated regulation of the metabolome and lipidome at the host-microbial interface.
Bäckhed F, Crawford PA.
Biochim Biophys Acta. 2010 Mar;1801(3):240-5. doi: 10.1016/j.bbalip.2009.09.009. Epub 2009 Sep 24.PMID: 19782151.

2009

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation.
Crawford PA, Crowley JR, Sambandam N, Muegge BD, Costello EK, Hamady M, Knight R, Gordon JI.
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11276-81. doi: 10.1073/pnas.0902366106. Epub 2009 Jun 22.PMID: 19549860. 

Hughey Lab

Coming soon!

OUR TEAM

Diana Cook

Diana Cook, Research Technician, Crawford and Puchalska lab

D. Andre d'Avignon

D. Andre d'Avignon, PhD, Senior Researcher, Crawford and Puchalska lab

Jacob Gillingham

Jacob Gillingham, Researcher, Crawford and Puchalska lab

Alisa Nelson

Alisa Nelson, PhD thesis student, Bioinformatics and Computational Biology Program, Crawford and Puchalska lab 

Ferrol Rome

Ferrol Rome, Researcher, Hughey lab

Morwena Jane Solivio

Morwena Jane Solivio, PhD, Researcher, Hughey lab

Blake Stagg

Blake Stagg, PhD thesis Student, Medical Scientist Training Program, Crawford and Puchalska lab

Animal Research Ethics

The Division is committed to best practices in research using animal models, ensuring that studies using animals are justified in their benefits, and research animal well-being is a priority.