PI: Rong Tian
Research in the Tian Laboratory focuses on the roles of cell metabolism and mitochondrial function in the pathogenesis of human diseases. We use multi-disciplinary approaches to examine the system by combining high resolution NMR techniques and metabolomics with the ability to target molecular regulatory mechanisms via genetic manipulation in animal models. Dr. Tian is also interested in bi-directional translational research between the bench and the bedside to elucidate the functional significance of altered cellular metabolism in ischemic heart disease, obesity, diabetes, and heart failure.
Energy metabolism is extremely robust in the heart. An adult human heart has the highest oxygen uptake rate in the body (~0.1ml O2/g/min at basal conditions); it generates and consumes (turnover) about 6 Kg of ATP daily, 15-20 times its own weight. The mitochondrion is the “powerhouse of the cell”; oxidative metabolism in the mitochondria supplies ~95% of ATP consumed by the heart. Impairment of cardiac metabolism and mitochondrial dysfunction have been found in a variety of disease conditions. There is, however, no therapy available for these defects. Our goal is to identify novel disease mechanisms that can be targeted for therapy. The lab is currently focusing on the following aspects:
Regulation of pathological cardiac hypertrophy by substrate metabolism: Pathological hypertrophy is a maladaptive response of the heart to chronic stress which ultimately leads to heart failure. Metabolic reprogramming is required for the development of pathological hypertrophy. Our studies aim at identifying and disrupting the molecular mechanisms linking the remodeling of glucose, lipid, and amino acid metabolism to the signaling pathways leading to pathological growth of the cardiac myocytes.
Mitochondrial mechanisms in stress response: We recently revealed a critical role of mitochondrial NAD(H) redox state in protein modification and stress tolerance. We are developing technology platforms with collaborators to investigate subcellular redox states and protein-protein interactions using novel biosensors and quantitative proteomics. Both basic and clinical research are ongoing to seek the molecular targets and therapeutic applications.
Metabolic reprogramming during development and disease: Cell metabolism reprograms during differentiation and maturation through complex mechanisms, some of which revert during aging or disease. We seek to define the role of several key players in metabolic reprogramming, e.g. the AMP-activated protein kinase (AMPK), an energy sensor and master regulator of metabolism, and epigenetic modifications by metabolism.
Current Laboratory Members
Chi Fung Lee
Chi Fung Lee joined the Tian Laboratory after receiving his PhD degree from the University of Texas Health Science Center at San Antonio, where he studied the roles of macrophage Nox4 in atherosclerosis. His work is focused on determining the mechanisms linking mitochondrial dysfunction to heart failure progression. He uses mouse models with primary (cardiac Complex I deficiency) and secondary (aortic constriction, TAC) mitochondrial dysfunction, both of which present protein hyperacetylation sensitive to NAD+. Chi Fung showed that elevation of cardiac NAD+ levels desensitizes mitochondrial permeability transition pore (mPTP) and improves cardiac function in TAC-stressed hearts. Guided by proteomics analysis, he now focuses on determining how NAD+-sensitive protein acetylation modulates heart failure progression by sensitizing mPTP and regulating cytosolic targets of protein hyperacetylation.
Dan Shao joined the Tian lab in February 2014, after completing her PhD training in cardiovascular research at the New Jersey Medical School in Rutgers. Dan is currently interested in glucose and branched chain amino acids in the heart, as well as fatty acid oxidation in high fat diet induced cardiomyopathy.
Outi Villet’s research focus is primarily cardiovascular medicine: cardiac metabolism (13C NMR), protection, surgery, and regeneration. Outi has extensive research experience working with animal models ranging from rodent vascular surgeries to cardiopulmonary bypass operations in swine. Special interests include hypoxia and ischemia in high altitude, cardiac surgery, and surgical device/method development for end state heart failure.
Gerhard Weber joined the Tian lab in 2017. After his medical school training in Germany and at Yale, he completed medical residencies in Germany and Brigham and Women’s Hospital in Boston, followed by a clinical Cardiology Fellowship at Stanford Hospital. His prior research expertise includes electrophysiology, computational biology, hematopoietic and stem cell development in zebrafish from his work at Boston Children’s Hospital, and cardiac disease phenotyping in iPSC cardiomyocytes which he conducted at Stanford. Gerhard’s research focus in the lab will be on the metabolic basis of cardiomyopathies.
Lauren Abell is a graduate student in UW Medicine – Pathology Department. She completed her B.S. in Biochemistry at the University of California in Santa Barbara. Lauren is currently interested in studying the effect of branched chain amino acids in cardiovascular metabolism.
Arianne Caudal is a graduate student in the Biochemistry Department at UW Medicine. In 2014, she received her B.S in Biochemistry and Molecular Biology from the University of California, Santa Barbara. Arianne is interested in answering fundamental questions regarding cellular metabolism, and how imbalances in metabolic homeostasis contribute to the progression of heart disease.
Michal received his PhD in 2016 from the University of Nottingham, UK, where he tried to establish how hypoxia regulates myocardial energy metabolism. He joined the Tian lab in 2016 and is exploring mechanisms by which altered myocardial metabolic reprogramming affects cardiac function.
Zhenglong Liu received his PhD in 2017 from the University of Chinese Academy of Sciences, where he worked on lipid metabolism in C. elegans and mice. Zhenglong has great interest in investigating how lipid metabolism is regulated and its relation to human diseases. Zhenglong joined the Tian lab in 2017 and is currently working on the roles that metabolites play in obesity and related diseases.
Yaxin received her PhD in 2016 from State University of New York Upstate Medical University, where she studied membrane proteostastic stress in mitochondria. Yaxin is very interested in the crosstalk between mitochondria and cytosol. She joined the Tian lab in 2017 and currently works on the mitochondrial metabolome.
After graduating from Kyoto University Faculty of Medicine, Kiyoto completed his residency and fellowship (cardiology) training at Hyogo Prefectural Amagasaki Hospital. He received his PhD from Kyoto University, where he studied the role of Nardilysin in energy metabolism. He joined the Tian lab in 2017 and is currently working on the role of branched chain amino acids in cardiovascular diseases
Julia Ritterhoff, PhD
Senior Research Fellow
Julia received her PhD in 2013 from the University of Heidelberg, Germany, where she was working on the anti-arrhythmic properties of S100A1 gene therapy for heart failure. Julia has a strong interest in understanding which factors contribute to cardiac disease progression and wants to exploit how cardiac metabolism exaggerates cardiac diseases. She joined the lab in 2015 and is currently working on the role of fatty acid metabolism in cardiac hypertrophy.
Matthew Walker received his PhD in cardiovascular pharmacology from the Medical College of Georgia (MCG). At MCG, he worked on testing a cell-permeable, mitochondrial-targeted peptide for its ability to protect the heart from ischemia/reperfusion injury. Currently, Matthew is focused on understanding the role mitochondrial dysfunction plays in the progression of heart failure. He has a particular interest in exploring the translational potential of metabolic and mitochondrial targeted therapies.
Bo Zhou joined the Tian Laboratory in 2015 where he is working on mitochondrial function and heart disease, specifically focusing on how mitochondrial complex v regulates the pathologic heart. Bo completed his PhD at Kumamoto University, and is interested in science education and would like to teach biology in the future. Bo likes to visit new places and will try weird food.
Sara Young is an undergraduate senior at the University of Washington studying Molecular Biology and Global Health. She is currently working toward a career in medicine and hopes to study cardiology and cardiac failure. Sara is very interested in cardiac research and investigating cardiac metabolism and cardiac diseases.
VISER Graduate Student
Mingyue Zhao is a graduate student from Sichuan University, and is currently in the Tian Laboratory through the Univeristy of Washington VISER programme. Mingyue completed her M.S. from the Medical School of Sichuan University in 2016. Mingyue is interested in mitochondrial function and its relation to human cardiovascular disease, and would like to focus in this field in the future.
Tian Lab Publications
- Wang W, Karamanlidis G, Tian R. Novel targets for mitochondrial medicine. Sci Transl Med. 2016 Feb 17; 8(326):326rv3
- Chiao YA, Kolwicz SC, Basisty N, Gagnidze A, Zhang J, Gu H, Djukovic D, Beyer RP, Raftery D, MacCoss M, et. al.
Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb 11;
- Lee CF, Tian R. Mitochondrion as a Target for Heart Failure Therapy- Role of Protein Lysine Acetylation. Circ J. 2015;79(9):1863-70. doi:10.1253/circj.CJ-15-0742. Epub 2015 Aug 4. PubMed PMID: 26248514.
- Roe ND, Standage SW, Tian R. The Relationship Between KLF5 and PPARα in the Heart: It’s Complicated. Circ Res. 2016 Jan 22;118(2):193-5. doi:10.1161/CIRCRESAHA.115.308069. PubMed PMID: 26838311; PubMed Central PMCID:PMC4743553.
- Kolwicz SC Jr, Airhart S, Tian R. Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure? Circulation. 2016 Jan 27. pii: CIRCULATIONAHA.116.021230. [Epub ahead of print] PubMed PMID: 26819375.
- Shao D, Tian R. Glucose Transporters in Cardiac Metabolism and Hypertrophy. Compr Physiol. 2015 Dec 15;6(1):331-51. doi: 10.1002/cphy.c150016. PubMed PMID:26756635.
- Ma X, Gao L, Karamanlidis G, Gao P, Lee CF, Garcia-Menendez L, Tian R, Tan K. Revealing Pathway Dynamics in Heart Diseases by Analyzing Multiple Differential Networks. PLoS Comput Biol. 2015 Jun 17;11(6):e1004332. doi: 10.1371/journal.pcbi.1004332. eCollection 2015 Jun.
- Kolwicz SC Jr, Liu L, Goldberg IJ, Tian R. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes. 2015 Aug;64(8):2817-27. doi: 10.2337/db14-1943. Epub 2015 Apr 9.
- Nabben M, van Bree BW, Lenaers E, Hoeks J, Hesselink MK, Schaart G, Gijbels MJ, Glatz JF, da Silva GJ, de Windt LJ, Tian R, Mike E, Skapura DG, Wehrens XH, Schrauwen P. Lack of UCP3 does not affect skeletal muscle mitochondrial function under lipid-challenged conditions, but leads to sudden cardiac death. Basic Res Cardiol. 2014 Nov;109(6):447. doi: 10.1007/s00395-014-0447-4. Epub 2014 Oct 25.
- Karamanlidis G, Garcia Menendez L, Kolwicz SC Jr, Lee CF, Tian R. Promoting PGC1α-driven Mitochondrial Biogenesis Is Detrimental In Pressure Overloaded Mouse Hearts. Am J Physiol Heart Circ Physiol. 2014 Aug 29. pii: ajpheart.00280.2014. [Epub ahead of print] PMID: 25172896
- Kim M, Hunter RW, Garcia-Menendez L, Gong G, Yang YY, Kolwicz SC Jr, Xu J, Wang W, Sakamoto K, Tian R. Mutation in the γ2-subunit of AMPK Stimulates Cardiomyocyte Proliferation and Hypertrophy Independent of Glycogen Storage. Circ Res. 2014 Mar 14;114(6):966-75. Epub 2014 Feb 6.
- Yu Q, Lee CF, Wang W, Karamanlidis G, Kuroda J, Matsushima S, Sadoshima J, Tian R. Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc. 2014 Jan 27;3(1):e000555. doi: 10.1161/JAHA.113.000555.
- Khan RS, Lin Y, Hu Y, Son NH, Bharadwaj KG, Palacios C, Chokshi A, Ji R, Yu S, Homma S, Schulze PC, Tian R, Goldberg IJ. Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function. Am J Physiol Endocrinol Metab. 2013 Dec;305(11):E1339-47.
- Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, Maccoss MJ, Rabinovitch PS. Global Proteomics and Pathway Analysis of Pressure-overload Induced Heart Failure and Its Attenuation by Mitochondrial Targeted Peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. Epub 2013 Aug 9. PMID: 23935006
- Kolwicz Jr. SC, Purohit S, Tian R. Cardiac Metabolism and its Interactions With Contraction, Growth, and Survival of Cardiomyocytes. Circ Res. 2013 Aug 16;113(5):603-16.
- Karamanlidis, G., Lee, C.F., Garcia-Menendez, L., Kolwicz Jr., S.C., Suthammarak, W., Gong, G., Sedensky, M.M., Morgan, P.G., Wang, W., Tian, R. Mitochondrial Complex I Deficiency Increases Protein Acetylation and Accelerates Heart Failure. Cell Metabolism, 2013.
- Garcia-Menendez, L., Karamanlidis, G., Kolwicz, S.C., Tian, R. (May 24 2013) Substrain specific response to cardiac pressure overload in C57BL/6 mice. American Journal of Physiology, 2013 May 24.
- Nowakowski, S.G., Kolwicz, S.C., Korte, F.S., Luo, Z., Robinson-Hamm, J.N., Page, J.L., Brozovich, F., Weiss, R.S., Tian, R., Murry, C.E., Regnier, M. Transgenic overexpression of ribonucleotide reductase improves cardiac performance. Proc. Natl. Acad. Sci. USA., 2013 Mar 25.
- Matsushima, S., Kuroda, J., Ago, T., Zhai, P., Ikeda, Y., Oka, S., Fong, G.H., Tian, R., Sadoshima, J., Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of HIF-1 and Upregulation of PPARα. Circular Research, 2013 Mar 8.
- Marney, L.C., Kolwicz, Jr., S.C., Tian, R., Synovec, R.E. Sample preparation methodology for mouse heart metabolomics using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Talanta, 2013,108:123–130.
- Kim, M., Tian, R. Transcript Variants dictate PRKAG2 cardiomyopathy? J. Mol. Cell. Cardiol,, 2012, Oct; 51(4):548-53. PMID: 21147121.
- Kolwicz, Jr., S.C., Olson, D.P., Marney, L.C., Garcia-Menendez, L. Synovec R.E., Tian, R. Cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2) prevents metabolic remodeling during pressure-overload hypertrophy. Circ. Res., 2012, Aug 31; 111(6): 728-38. PMID: 22730442.
- Kim, M,, Shen, M., Ngoy, S., Karamanlidis, G., Liao, R., Tian, R., AMPK Isoform expression in the normal and failing hearts. J. Mol. Cell. Cardiol., 2012 May;52(5):1066-73. Epub 2012 Jan 31. PMID: 22314372.
- Yoshioka, J., Chutkow, W.A., Lee, S., Kim, J.B., Yan, J., Tian, R., Lindsey, M.L., Feener, E.P., Seidman, C.E., Seidman, J.G., Lee, R.T. Deletion of Thioredoxin-Interacting Protein Impairs Mitochondrial Function but Protects the Myocardium from Ischemia-Reperfusion Injury. J. Clin. Invest., 2012 Jan 3; 122(1):267-79. Epub 2011 Dec 27. PMID: 22201682.
- Karamanlidis, G., Bautista-Hernandez, V., Fynn-Thompson, F., Del Nido, P., Tian, R. Impaired Mitochondrial Biogenesis Precedes Heart Failure in Right Ventricular Hypertrophy in Congenital Heart Disease. Circ. Heart Fail., 2011 Nov 1; 4 (6): 707-13. Epub 2011 Aug 12 PMID: 21840936.
- Dzeja, P.P., Hoyer, K., Tian, R., Zhang, S., Nemutlu, E., Spindler, M., Ingwall, J.S. Rearrangement of energetic and substrate utilization networks compensate for chronic myocardial creatine kinase deficiency. J. Physiol., 2011 Nov 1; 589 (Pt 21): 5193-211 Epub 2011 Aug 30. PMID: 21878522.
- Pinz, I., Tian, R., Belke, D., Swanson, E., Dillmann, W., Ingwall, J.S. Compromised myocardial energetics in hypertrophied mouse hearts diminish the beneficial effect of overexpressing SERCA2a. J. Biol. Chem., 2011 Mar 25; 286(12):10163-8. Epub 2011 Jan 29. PMID: 21278384 PMCID: PMC3060468.
- Xie, Z., Lau, K., Eby, B., Lozano, P., He, C., Pennington, B., Li, H., Rathi, S., Dong, Y., Tian, R., Kem, D., Zou, M.H. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes, 2011 Jun; 60(6):1770-8. Epub 2011 May 11. PMID: 21562078 PMCID: PMC3114402.
- Kolwicz Jr., S.C., Tian, R. Glucose metabolism and cardiac hypertrophy. Cardiovasc. Res., 2011 May 1; 90(2):194-201. PMID:21502371 [PubMed- in process].
- Kim, M., Tian, R.Targeting AMPK for cardiac protection: Opportunities and Challenges. J. Mol. Cell. Cardiol., 2011 Oct; 5 (4): 548-53. Epub 2010 Dec 13 PMID:21147121.
- Kolwicz Jr., S.C., Tian, R. Assessment of cardiac function and energetics in isolated mouse hearts using 31P NMR spectroscopy. J. Vis. Exp., 2010 Aug 31;(42). pii: 2069. doi: 10.3791/2069. PMID: 20834220.