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McKinsey Lab


Our lab is focused on​ underst​anding the signaling and gene regulatory mechanisms that control heart failure and associated disorders. We are particularly interested in the​ role of epigenetics in regulating the pathological cardiac hypertrophy and fibrosis that is associated with heart failure. Nuclear DNA is wound around proteins called histones to form chromatin, and post-translational modification of histones represents one epigenetic mechanism for altering gene expression. Among the enzymes that target histones are histone deacetylases (HDACs), histone acetyltransferases (HATs) and histone methyltransferases. We use molecular biology, biochemistry and pharmacology to address the roles of these and other epigenetic modifiers in the control of gene expression in the heart, and extend our findings to surgical, transgenic and gene knockout models of heart failure. Our animal model studies involve echocardiographic and catheter-based measurements of heart function​.

We are also interested in the mechanisms whereby signals derived from cell surface receptors are conveyed to histone-modifying enzymes by proteins kinases and phosphatases. The long-term goal of our work is to translate basic discoveries to novel therapies for patients with heart failure, which afflicts millions of adults in the U.S. and is associated with a 5-year mortality rate of nearly 50%. As such, our lab has established core expertise to enable in vitro, cellular and in vivo assessment of experimental small molecule compounds in support of early stage drug discovery.

Our lab emphasizes teamwork and camaraderie, thus creating an exciting environment for students and postdoctoral trainees. ​
Timothy A. McKinsey, Ph.D.
School of Medicine, Division of Cardiology 
University of Colorado Denver 
Anschutz Medical Campus 
12700 E. 19th Ave 
Aurora, CO 80045-0508 
Tel: (303) 724-5476 

2016 Holiday Christmas Dinner 


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2017 lab outing 
Rockies baseball game
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2017 FASEB meeting in Montana
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2017 Hiking in Boulder


 

Timothy McKinsey 

Timothy McKinsey, Ph.D.
Associate Professor
Associate Division Head for Translational Research

Department of Medicine
Division of Cardiology​

Member/Trainin​g Faculty:
- Molecular and Cellular Pharmacology PhD Program
- Biomedical Sciences PhD Training Program
- Medical Scientist MD/PhD Training Program

timothy.mckinsey@ucdenver.edu
 
Maria Cavasin, Ph.D.

Senior Research Associate

Department of Medicine
Division of Cardiology

maria.cavasin@ucdenver.edu
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Post Doctoral Fellows

​​ Rushita Bagchi, Ph.D.

Department of Medicine
Division of Cardiology

B.S. University of Baroda (India)
M.S. University of Baroda (India)
Ph.D. University of Manitoba (Canada)

rushita.bagchi@ucdenver.edu​
Ying Hsi (Alvin) Lin, Ph.D.

Department of Medicine
Division of Cardiology

B.S.  National Taiwan University 
M.S. National Taiwan University
Ph.D. University of Illinois at Chicago

ying.lin@ucdenver.edu
​​
Tianjing Hu, Ph.D. 

Department of Medicine
Division of Cardiology

B.S. Biotechnology, Bejing Normal University (Bejing, China)
Ph.D. Biochemisty, University of Colorado Boulder

tianjing.hu@ucdenver.edu
Marina Felisbino, Ph.D.

Department of Medicine
Division of Cardiology

B.S. Biology
M.S. Structural and Cellular Biology
Ph.D. Structural and Cellular Biology, University of Campinas (Brazil)

marina.felisbina@ucdenver.edu​
Jennifer Major.png Jennifer Major, Ph.D. 

Department of Medicine
Division of Cardiology

B.S. Biology
M.S. Cellular and Molecular Medicine
Ph.D. Cellular and Molecular Medicine, University of Ottawa

jennifer.major@ucdenver.edu​
Joshua Travers Headshot.jpg ​​​Josh Travers, Ph.D.

Department of Medicine
Division of Cardiology

B.S. Biotechnology, Rochester Institute of Technology
Ph.D. Pharmacology, University of Cincinnati

josh.travers@ucdenver.edu​​
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Research Staff


​​Sara Wennersten, B.S.

Department of Medicine
Division of Cardiology

B.S. Human Biology, Michigan State University
​​
sara.wennersten@ucdenver.edu
 
Korey Haefner, B.S.

Department of Medicine
Division of Cardiology

B.S. University of Colorado Boulder

korey.haefner@ucdenver.edu​​
 


Former Lab Members​

Matthew Stratton, Ph.D.

Current Position:
Assistant P​rofessor
Ohio State University

B.S. Duquesne University
M.S. University of Wyoming
Ph.D. Colorado State University

matthew.stratton@osumc.edu
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Weston Blakeslee, Ph.D.

Current Position:
Director of Clinical Pharmacology, RxREVU

B.S. University of Colorado Boulder
Ph.D. University of Colorado Denver-AMC​

weston.blakeslee@rxrevu.com

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Bradley Ferguson, Ph.D.

Current Position:
Assistant Professor,
University of Nevada, Reno 

B.S. Appalachian State University
M.S./Ph.D. University of North Carolina-Greensboro

bferguson@unr.edu

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Sean Wickers

University of Denver​


 alt= Katherine Schuetze, M.D.

B.S. University of Colorado Boulder
M.D. University of Colorado Denver-AMC
Residency-University of Michigan

katherine.schuetze@ucdenver.edu​​
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Kim Demos-Davies, B.A.

Current Position:
Graduate Student,
DVM/Ph.D. Program
University of Minnesota

B.A. University of Colorado-Boulder​

Friederike Schreiter, M.S.

B.S. University of Heidelberg, Germany
M.S. University of Heidelberg, Germany​



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2018

Histone deacetylase governs diastolic dysfunction through a nongenomic mechanism​. Jeong MY, Lin YH, Wennersten SA, Mo​nzani V, Saripalli C, Mascagni P, Reece BT, Ambardeker AV, Granzier HL, Dinarello CA, McKinsey TA. 2018 Sci Transl Med. Feb 07;10(427). DOI: 10.1126/scitranslmed.aao0144

2017

BRD4 inhibition for the treatment of pathological organ fibrosis.Stratton MS, Haldar SM, McKinsey TA. 2017 F1000Res. 2​017 Jun 28;6. pii: F1000 Faculty Rev-1015. doi: 10.12688/f1000research.11339.1. eCollection 2017. Review.​

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.Blakeslee WW, Demos-Davies KM, Lemon DD, Lutter KM, Cavasin MA, Payne S, Nunley K, Long CS, McKinsey TA, Miyamoto SD. 2017Pediatr Res.  May 26. doi: 10.1038/pr.2017.126. 

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure.Duan Q, McMahon S, Anand P, Shah H, Thomas S, Salunga HT, Huang Y, Zhang R, Sahadevan A, Lemieux ME, Brown JD, Srivastava D, Bradner JE, McKinsey TA, Haldar SM. 2017 Sci Transl Med. May 17;9(390). pii: eaah5084. doi: 10.1126/scitranslmed.aah5084.

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts.Schuetze KB, Stratton MS, Blakeslee WW, Wempe MF, Wagner FF, Holson EB, Kuo YM, Andrews AJ, Gilbert TM, Hooker JM, McKinsey TA. 2017 J Pharmacol Exp Ther.  Apr;361(1):140-150. doi: 10.1124/jpet.116.237701. Epub 2017 Feb 7.

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Zeng Q, Song R, Fullerton DA, Ao L, Zhai Y, Li S, Ballak DB, Cleveland JC Jr, Reece TB, McKinsey TA, Xu D, Dinarello CA, Meng X. 2017 Proc Natl Acad Sci U S A.  Feb 14;114(7):1631-1636. doi: 10.1073/pnas.1619667114. Epub 2017 Jan 30.

Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension. Aiello RJ, Bourassa PA, Zhang Q, Dubins J, Goldberg DR, De Lombaert S, Humbert M, Guignabert C, Cavasin MA, McKinsey TA, Paralkar V. 2017 J Pharmacol Exp Ther.  Feb;360(2):267-279. doi: 10.1124/jpet.116.237933. 

Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes.Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, García S, Malvar Fernandez B, McKinsey TA, Tak PP, Fossati G, Mascagni P, Baeten DL, Reedquist KA. 2017Ann Rheum Dis. Jan;76(1):277-285. doi: 10.1136/annrheumdis-2015-209064. 


2016

The potential of targeting epigenetic regulators for the treatment of fibrotic cardiac diseases. Schuetze KB, Koch KA, McKinsey TA. Future Med Chem. Sep;8(13):1533-6. doi: 10.4155/fmc-2016-0144. Epub 2016 Aug 24. No abstract available.

Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA.Stratton MS, Lin CY, Anand P, Tatman PD, Ferguson BS, Wickers ST, Ambardekar AV, Sucharov CC, Bradner JE, Haldar SM, McKinsey TA. 2016 Cell Rep.  Aug 2;16(5):1366-78. doi: 10.1016/j.celrep.2016.06.074. 

Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Nozik-Grayck E, Woods C, Stearman RS, Venkataraman S, Ferguson BS, Swain K, Bowler RP, Geraci MW, Ihida-Stansbury K, Stenmark KR, McKinsey TA, Domann FE. 2016 Am J Physiol Lung Cell Mol Physiol. Jul 1;311(1):L124-34. doi: 10.1152/ajplung.00263.2015. 

Myofibril growth during cardiac hypertrophy is regulated through dual phosphorylation and acetylation of the actin capping protein CapZ. Lin YH, Warren CM, Li J, McKinsey TA, Russell B.  2016 Cell Signal.  Aug;28(8):1015-24. doi: 10.1016/j.cellsig.2016.05.011. 

Discovery of novel small molecule inhibitors of cardiac hypertrophy using high throughput, high content imaging.Reid BG, Stratton MS, Bowers S, Cavasin MA, Demos-Davies KM, Susano I, McKinsey TA. 2016 J Mol Cell Cardiol. Aug;97:106-13. doi: 10.1016/j.yjmcc.2016.04.015.

Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation.​ Horita H, Wysoczynski CL, Walker LA, Moulton KS, Li M, Ostriker A, Tucker R, McKinsey TA, Churchill ME, Nemenoff RA, Weiser-Evans MC. Nat Commun. 2016 Mar 4;7:10830. doi: 10.1038/ncomms10830. PMID: 26940659

Epigenetic regulation of cardiac fibrosis.​ Stratton MS, McKinsey TA. J Mol Cell Cardiol. 2016 Mar;92:206-13. doi: 10.1016/j.yjmcc.2016.02.011. Epub 2016 Feb 12. Review. PMID: 26876451​


2015
High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling.Zhao Y, Londono P, Cao Y, Sharpe EJ, Proenza C, O'Rourke R, Jones KL, Jeong MY, Walker LA, Buttrick PM, McKinsey TA, Song K. Nat Commun. 2015 Sep 10;6:8243. doi: 10.1038/ncomms9243. PMID: 26354680

TNAP: a new player in cardiac fibrosis? Focus on "Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts".Schuetze KB, McKinsey TA. Am J Physiol Cell Physiol. 2015 Aug 1;309(3):C137-8. doi: 10.1152/ajpcell.00167.2015. Epub 2015 Jun 24. PMID: 26108666

Emerging roles for histone deacetylases in pulmonary hypertension and right ventricular remodeling (2013 Grover Conference series).Cavasin MA, Stenmark KR, McKinsey TA. Pulm Circ. 2015 Mar;5(1):63-72. doi: 10.1086/679700. Review. PMID: 25992271

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner.Stauffer BL, Dockstader K, Russell G, Hijmans J, Walker L, Cecil M, Demos-Davies K, Medway A, McKinsey TA, Sucharov CC. Biochem Biophys Res Commun. 2015 Jun 26;462(2):131-7. doi: 10.1016/j.bbrc.2015.04.106. Epub 2015 Apr 29. PMID: 25935483

Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement.Salian-Mehta S, Xu M, McKinsey TA, Tobet S, Wierman ME. J Biol Chem. 2015 May 29;290(22):14045-56. doi: 10.1074/jbc.M115.640482. Epub 2015 Apr 14. PMID: 25873389

Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle. Lemon DD, Harrison BC, Horn TR, Stratton MS, Ferguson BS, Wempe MF, McKinsey TA. FEBS Lett. 2015 Apr 28;589(10):1080-8. doi: 10.1016/j.febslet.2015.03.017. Epub 2015 Mar 25. PMID: 25816750 

Acetyl-lysine erasers a​nd readers in the control of pulmonary hypertension and right ventricular hypertrophy.​ Stratton MS, McKinsey TA. Biochem Cell Biol. 2015 Apr;93(2):149-57. doi: 10.1139/bcb-2014-0119. Epub 2014 Dec 16. Review. PMID: 25707943 

Non-sirtuin histone deacetylases in the control of cardiac aging. Ferguson BS, McKinsey TA. J Mol Cell Cardiol. 2015 Jun;83:14-20. doi: 10.1016/j.yjmcc.2015.03.010. Epub 2015 Mar 16. Review. PMID: 25791169 

AKT Network of Genes and Impaired Myocardial Contractility During Murine Acute Chagasic Myocarditis.Henao-Martínez AF, Agler AH, Watson AM, Hennessy C, Davidson E, Demos-Davies K, McKinsey TA, Wilson M, Schwartz DA, Yang IV. Am J Trop Med Hyg. 2015 Mar;92(3):523-9. doi: 10.4269/ajtmh.14-0433. Epub 2015 Jan 12. PMID: 25582694 



2014

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. McLendon PM, Ferguson BS, Osinska H, Bhuiyan MS, James J, McKinsey TA, Robbins J. Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):E5178-86. doi: 10.1073/pnas.1415589111. Epub 2014 Nov 17. PMID: 25404307

Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Angiolilli C, Grabiec AM, Ferguson BS, Ospelt C, Malvar Fernandez B, van Es IE, van Baarsen LG, Gay S, McKinsey TA, Tak PP, Baeten DL, Reedquist KA. Ann Rheum Dis. 2014 Dec 1. pii: annrheumdis-2014-205635. doi: 10.1136/annrheumdis-2014-205635. [Epub ahead of print] PMID: 25452308 

Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism. Blakeslee WW, Wysoczynski CL, Fritz KS, Nyborg JK, Churchill ME, McKinsey TA. Cell Signal. 2014 Dec;26(12):2912-20. doi: 10.1016/j.cellsig.2014.09.005. Epub 2014 Sep 16. PMID: 25220405 

Reversal of severe angioproliferative pulmonary arterial hypertension and right ventricular hypertrophy by combined phosphodiesterase-5 and endothelin receptor inhibition. Cavasin MA, Demos-Davies KM, Schuetze KB, Blakeslee WW, Stratton MS, Tuder RM, McKinsey TA. J Transl Med. 2014 Nov 26;12:314. doi: 10.1186/s12967-014-0314-y. PMID: 25425003 

BET-ting on chromatin-based therapeutics for heart failure. Haldar SM, McKinsey TA. J Mol Cell Cardiol. 2014 Sep;74:98-102. doi: 10.1016/j.yjmcc.2014.05.002. Epub 2014 May 14. Review. PMID: 24838003 

HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling. Demos-Davies KM, Ferguson BS, Cavasin MA, Mahaffey JH, Williams SM, Spiltoir JI, Schuetze KB, Horn TR, Chen B, Ferrara C, Scellini B, Piroddi N, Tesi C, Poggesi C, Jeong MY, McKinsey TA. Am J Physiol Heart Circ Physiol. 2014 Jul 15;307(2):H252-8. doi: 10.1152/ajpheart.00149.2014. Epub 2014 May 23. PMID: 24858848 

Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic kidney disease-induced vascular calcification. Miyazaki-Anzai S, Masuda M, Demos-Davies KM, Keenan AL, Saunders SJ, Masuda R, Jablonski K, Cavasin MA, Kendrick J, Chonchol M, McKinsey TA, Levi M, Miyazaki M. J Am Heart Assoc. 2014 Jun 24;3(3):e000949. doi: 10.1161/JAHA.114.000949. PMID: 24963104 

Targeting cardiac fibroblasts to treat fibrosis of the heart: focus on HDACs. Schuetze KB, McKinsey TA, Long CS. J Mol Cell Cardiol. 2014 May;70:100-7. doi: 10.1016/j.yjmcc.2014.02.015. Epub 2014 Mar 11. Review. PMID: 24631770 

Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes.Williams SM, Golden-Mason L, Ferguson BS, Schuetze KB, Cavasin MA, Demos-Davies K, Yeager ME, Stenmark KR, McKinsey TA. J Mol Cell Cardiol. 2014 Feb;67:112-25. doi: 10.1016/j.yjmcc.2013.12.013. Epub 2013 Dec 26. PMID: 24374140 ​​

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​​Cardiac Physiology​​

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Cardiac Fibrosis​

 
 

Cardiac Hypertrophy​

 

​Pharmacology and High Throughput Chemical Biology

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​Signaling and Gene Regulation

 
 
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