Ulrike Mende is interested in the functional role of G proteins (GTP-binding proteins) and their regulators (Regulators of G protein Signaling) in the heart. They are crucial for the transmission of signals from the cell surface to the inside. Changes in their amount or function often lead to compromised cardiac function and disease, such as hypertrophy and failure. Our goal is to delineate the underlying molecular mechanisms and devise new therapeutic strategies.

Biography

Dr. Mende attended Medical School at the University of Hamburg in Germany, followed by 7 years postdoctoral training in the Department of Pharmacology at the University of Hamburg and in the Cardiovascular Division of Brigham and Women's Hospital and Harvard Medical School. She launched a career as an independent scientist and principal investigator at Brigham and Women's Hospital and was promoted at Harvard Medical School to Instructor in 1995 and to Assistant Professor of Medicine in 2000. In 2005, Dr. Mende was recruited by Rhode Island Hospital and Brown Medical School as an Associate Professor of Medicine to help establish a new Cardiovascular Research Center. Her research focuses on cell signaling in heart cells under normal and pathophysiological conditions. Her work has been funded by the American Heart Association (AHA) and the National Institutes of Health (NIH), where she has also been serving as grant reviewer for many years.

Research Description

Dr. Mende has a longstanding interest in myocardial signaling mechanisms that control cardiac growth and function under normal and pathophysiological conditions. Signal transduction via G protein-coupled receptors is one of the most important mechanisms of signal transfer across the plasma membrane in virtually all cells, including heart cells. Heterotrimeric GTP-binding proteins (G proteins) act as relay switches that are responsible for proper transduction of cell surface signals to specific ion channels and/or second messenger pathways inside the cell. G proteins are under the control of Regulators of G protein Signaling (RGS proteins). We and others have shown that changes in the expression level, composition and/or function of G proteins and RGS proteins often lead to alterations in cell signaling with subsequent changes in cardiac function.

The major focus in my laboratory over the past 10 years has been to better understand the molecular mechanisms that link derangement in G protein-mediated myocyte signaling to cardiac hypertrophy and failure. To that end, we have been utilizing a wide range of techniques from different disciplines, including gain- and loss-of-function approaches in vitro (primary cultures of cardiac myocytes) and in vivo (genetically modified mouse models), molecular biological approaches to examine gene expression and regulation, biochemical approaches to measure enzyme function and second messenger levels and physiological approaches to assess single myocyte and cardiac growth and contraction. Our long-term goal is to identify potential new targets and strategies for pharmacological or genetic therapies.

We recently expanded our investigations from cardiac myocytes to fibroblasts, the other major cell type in the heart. Importantly, both cell types are always in close contact with each other and exert mutual regulatory control via direct cell-cell contact and paracrine factors. Myocyte-fibroblast cross-regulation and its importance in the development of cardiac disease are not well understood. We have been developing nocel experimental 2D and 3D in vitro models to address these questions in more detail.

Awards

Honorary M.A. ad eundum (Brown University), 2007

Fellow of the American Heart Association (FAHA, American Heart Association), 2006

9th Annual AstraZeneca Cardiovascular Young Investigators' Forum, 2nd Prize (AstraZeneca), 2003

New Investigator Travel Award (American Heart Association), 2002

New England Cardiovascular Research Competition, 3rd Prize (AstraZeneca), 1998

Louis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators, Finalist (American Heart Association), 1998

Thomas W. Smith Fellowship Award (Brigham and Women's Hospital, Boston), 1998-1999

Postdoctoral Fellowship Award (Deutsche Forschungsgemeinschaft), 1992-1994

Dr. Martini Award (University of Hamburg, Germany), 1991

Affiliations

International Society for Heart Research (since 2003)
Heart Failure Society of America (2003-2004)
American Society for Biochemistry and Molecular Biology (1996-2011)
American Heart Association (since 1995)
German Society of Heart and Circulation Research (since 1991)
German Society of Pharmacology and Toxicology (1990-2000)
American Physiological Society (since 2012)

Funded Research

Current Research Funding:

Title: G protein-mediated Signaling and its Regulation by RGS Proteins in Cardiac Fibroblasts.
Grant/Source: #0740098N; American Heart Association, Established Investigator Award
Dates: 1/1/07-6/30/12 (no cost extension)
Amount: $90,909 per year (direct)
Role: Principal Investigator

Title: RGS Regulation of Cardiac Signaling and Hypertrophy
Grant/Source: 1RO1 HL080127; NIH
Dates: 5/1/06-4/30/12 (no cost extension)
Amount: $250,000 per year (direct)
Role: Principal Investigator

Title: COBRE for Perinatal Biology
Source: P20 RR018728; NIH
Dates: 9/16/2008-7/31/2013
Amount: partial salary support
Role: Faculty Mentor and Executive Committee Member (PI: Dr. J. Padbury)

Title: Sex Hormones and Cardiac Arrhythmia in Transgenic LQT2 Rabbits
Grant/Source: R01 HL093205; NIH
Dates: 4/1/2009 – 3/31/2014
Amount: partial salary support
Role: Co-Investigator (PI: Dr. G. Koren)

Title: Novel Micropatterned Culture Model for Developing New Therapeutic Strategies for Sudden Cardiac Death.
Grant/Source: Brown Research Seed Fund; Brown University
Dates: 3/1/2011 – 8/30/2012 (no cost extension)
Amount: $90,000 per year (direct)
Role: Co-Investigator (PI: Dr. D. Hoffman-Kim)


Past Research Funding:

Title: High Content Drug Screening with Cardiac Tissue
Grant/Source: R43 HL093939; NIH
Dates: 9/1/2008 – 9/31/2010
Amount: $100,000 total (direct)
Role: Co-Investigator (PI: Dr. H. Vandenburgh)

Title: Muscarinic Signaling: Regulation of Ventricular Function
Grant/Source: 1 R01 HL72174; National Institutes of Health (NIH)
Dates: 7/1/03-6/30/08
Amount: $225,000 per year (direct)
Role: Principal Investigator

Title: Regulation of Cardiomyocyte Signaling and Function by Endogenous Regulators of G Protein Signaling
Grant/Source: #05555817T; American Heart Association, Grant-in-Aid
Dates: 7/1/05-6/3/08 (returned 12/31/06 to accept an AHA-EIA).
Amount: $55,500 per year (direct)
Role: Principal Investigator

Title: Cellular and Molecular Mechanisms Underlying Heart Failure Caused by Expression of a Constitutively Active G Protein alphaq Subunit (Project 4 of SCOR in Heart Failure)
Grant/Source: P50 HL52320; NIH
Dates: 2/1/00-1/31/05
Amount: $219,371 per year (direct)
Role: Principal Investigator

Title: Isolated Myocyte and Whole Heart Physiology (Core B of SCOR in Heart Failure)
Grant/Source: P50 HL52320; NIH
Dates: 2/1/00-1/31/05
Amount: $77,312 per year (direct)
Role: Principal Investigator (together with Dr. Richard T. Lee)

Title: Modulation of G Protein-Mediated Signal Transduction in Heart Cells by GS Proteins
Grant/Source: #9930032N; American Heart Association, Scientist Development Grant
Dates: 1/1/99-12/31/03
Amount: $59,091 per year (direct)
Role: Principal Investigator

Title: Activating and Inhibiting Mutations of G Proteins Targeted to the Hearts of Transgenic Mice
(Project 4 of Specialized Centers of Research (SCOR) in Heart Failure)
Grant/Source: P50 HL52320; NIH
Dates: 2/1/95-1/31/00
Amount: $198,879 per year (direct)
Role: Co-Investigator (PI: Dr. Eva J. Neer)

Title: Myocyte Culture and Biophysical Analysis (Core B of SCOR in Heart Failure)
Grant/Source: P50 HL52320; NIH
Dates: 2/1/95-2/31/00
Amount: $87,506 per year (direct)
Role: Principal Investigator (as of 1/1/98)

Teaching Experience

My academic teaching portfolio includes the entire spectrum of Basic and Clinical Pharmacology and Toxicology for medical students that I taught in the traditional lecture format in Germany from 1988 to 1992. In 1993, I had the opportunity to gain experience with the problem-oriented learning approach at Harvard Medical School by leading a tutorial group in the Principles in Pharmacology course for 1st year medical students. From 2001-2005, I was on the faculty for the Integrated Human Physiology course as tutor and was nominated by Harvard Medical School students for teaching awards in 2002 and 2004. Since I joined the faculty of Brown University, I am involved in teaching undergraduate, graduate and medical students through the courses listed below.
In addition, and on a more continuous basis, I have been teaching postdoctoral fellows, students and technical research assistants in my laboratory by guiding them in their research and serving as their mentor. I am also a readily available resource for other Principal Investigators and members of their laboratories.

Courses Taught

• Directed Research/Independent Study (Biol 1950/1960)
• Integrated Medical Sciences III - Cardiovascular (BIOL 3660)
• Receptor, Channels and Signaling (BIOL 2170)

Selected Publications

• Mackiewicz U, Czarnowska E, Brudek M, Pająk B, Duda M, Emanuel K, Csanyi G, Fedorowicz A, Grochal E, Tyrankiewicz U, Skórka T, Mende U, Lewartowski B, Chłopicki S. Preserved cardiomyocyte function and altered desmin pattern in transgenic mouse model of dilated cardiomyopathy. J Mol Cell Cardiol 2012; 52(5): 978-987.(2012)
• Desroches BR, Zhang P, Choi B, King ME, Maldonado AE, Li W, Rago A, Liu GX, Nath N, Hartmann KM, Yang B, Koren G, Morgan JR, Mende U. Functional scaffold-free 3D cardiac microtissues: a novel model for the investigation of heart cells. Am J Physiol Heart Circ Physiol 2012; 302(10): H2031-H2042.(2012)
• Park-Windhol C, Zhang P, Zhu M, Su J, Chaves Jr L, Maldonado AE, King ME, Rickey L, Cullen D , Mende U. Gq/11-mediated signaling and hypertrophy in mice with cardiac-specific transgenic RGS2 expression. PLoS ONE 2012; 7: e40048.(2012)
• Zhang P, Su J, Mende U. Cross-regulation between cardiac myocytes and fibroblasts. Am J PhysiolHeart Circ Physiol: 2012 Oct 12. [Epub ahead of print].(2012)
• Pinz I, Zhu M, Mende U, Ingwall J. An improved isolation procedure for adult mouse cardiomyocytes. Cell Biochem Biophys 2011; 61: 93-101.(2011)
• Chakir K, Zhu W, Tsang S, Woo AY, Yang D, Wang X, Zeng X, Rhee MH, Mende U, Koitabashi N, Takimoto E, Blumer KJ, Lakatta EG, Kass DA, Xiao RP. RGS2 is a primary terminator of β2-adrenergic receptor-mediated Gi signaling. J Mol Cell Cardiol 2011; 50(6): 1000-1007.(2011)
• Hirose M, Takeishi Y, Niizeki T, Nakada T, Shimojo H, Kubota I, Mende U, Yamada M. Diacylglyerol kinase zeta inhibits ventricular tachyarrythmias in a mouse model of heart failure: Roles of canonical transient receptor potential (TRPC) channels. Circ J 2011; 75:2333-2342.(2011)
• Zhang P, Su J, King ME, Maldonado Lopez AE, Park C, Mende U. Regulator of G protein signaling 2 is a functionally important negative regulator of Angiotensin II-induced cardiac fibroblast responses. Am J Physiol Heart Circ Physiol 2011; 301: H147-H156.(2011)
• Zhang P, Mende U. Regulators of G Protein Signaling in the heart and their potential as therapeutic targets. Circ Res 2011; 109: 320-333.(2011)
• Hirose M, Takeishi Y, Niizeki T, Shimojo H, Nakada T, Kubota I,Nakayama J, Mende U, Yamada M. Diacylglyerol Kinase zeta inhibits Gaq-induced atrial remodeling in transgenic mice. Heart Rhythm 2009; 6: 78-84.(2009)
• Niizeki T, Takeishi Y, Kitahara T, Arimoto T, Koyama Y, Goto K, Mende U, Kubota I. Diacylglyerol Kinase zeta rescues Gaq-induced heart failure in transgenic mice. Circ J 2008; 72: 309-317.(2008)
• Drelicharz L, Kozlovski V, Skorka T, Heinze-Paluchowska S, Jasinski A, Gebska A, Guzik T, Olszanecki R, Wojnar L, Mende U, Csanyi G, Chlopicki S. NO and PGI(2) in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy. Basic Res Cardiol 2008; 103: 417-430.(2008)
• Zhu M, Gach A, Liu GX, Xu X, Lim CC, Zhang JX, Mao L, Chuprun K, Koch WJ, Liao R, Koren G, Blaxall BC, Mende U. Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active Gao protein. Am J Physiol Heart Circ Physiol 2008; 294: H1335-H1347.(2008)
• Fish S, Gray S, Heymans S, Wang B, Haldar S, Pfister O, Cui L, Kumar A, Lin Z, Sen-Banerjee S, Das H, Petersen CA, Mende U, Burleigh BA, Zhu Y, Pinto Y, Liao R, Jain M. Kruppel-like factor KLF 15 is a novel regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci USA. 2007; 104(17): 7074-7079.(2007)
• Schmitt JP, Debold EP, Ahmad F, Armstrong A, Frederico A, Conner DA, Mende U, Lohse MJ, Warshaw D, Seidman CE, Seidman JG. Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function. Proc Natl Acad Sci USA. 2006; 103(39): 14525-14530.(2006)
• Zhang W, Anger T, Su J, Hao J, Xu X, Zhu M, Gach A, Cui L, Liao R, Mende U. Selective loss of fine-tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. J Biol Chem. 2006; 281(9): 5811-5820.(2006)
• Hao J, Zhang W, Michalek C, Zhu M, Xu X, Mende U. Regulation of cardiomyocyte signaling by RGS proteins: differential selectivity towards G proteins and susceptibility to regulation. J Mol Cell Cardiol. 2006; 41: 51-61.(2006)
• Anger T, Zhang W, Mende U. Differential contribution of GTPase activation and effector antagonism to the inhibitory effect of RGS proteins on Gq-mediated signaling in vivo. J Biol Chem. 2004; 279(6): 3906-3915.(2004)
• Carvalho-Bianco SD, Kim BW, Zhang JX, Harney JW, Ribeiro RS, Gereben B, Bianco AC, Mende U, Larsen PR. Chronic cardiac-specific thyrotoxicosis increases myocardial b-adrenergic responsiveness. Mol Endocrinol. 2004; 18(7): 1840-1849.(2004)
• Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003; 299(5611): 1410-1413.(2003)
• Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest. 2002; 109(8): 1013-1020.(2002)
• Gehrmann J, Meister M, Maguire CT, Martins DC, Hammer PE, Neer EJ, Berul CI, Mende U. Impaired parasympathetic heart rate control in mice with a reduction of functional G protein bg subunits. Am J Physiol Heart Circ Physiol. 2002; 282(2): H445-H456.(2002)
• Mende U, Semsarian C, Martins DC, Kagen A, Duffy C, Schoen FJ, Neer EJ. Dilated cardiomyopathy in two transgenic mouse lines expressing activated G protein aq: lack of correlation between phospholipase C activation and the phenotype. J Mol Cell Cardiol. 2001; 33(8): 1477-1491.(2001)
• Greif GJ, Sodickson DL, Bean BP, Neer EJ, Mende U. Altered regulation of potassium and calcium channels by GABAB and adenosine receptors in hippocampal neurons from mice lacking Gao. J Neurophysiol. 2000; 83(2): 1010-1018.(2000)