Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration (Ivor J. Benjamin, Director)

Our laboratory focuses on the pathogenic mechanisms involving selected stress response pathways (e. g., heat shock response, redox state) induced at onset of disease and their subsequent dysregulation culminating in disease progression. We are specifically interested in deciphering the genetic, molecular and metabolic events that promote adverse remodeling in response to acquired conditions (e.g., heart attacks) and inheritable (e.g., cardiomyopathy) disorders. From such insights of the causal mechanisms using complementary model systems (i.e., yeast, flies, mice), our multidisciplinary program and translational studies are seeking to exploit innovative strategies (e.g., small molecule targeting, cell regeneration) for diagnostic, therapeutic, and ultimately disease prevention.

Work in our laboratory focuses on three complementary themes linked to protein misfolding diseases: 1) small heat shock proteins (sHSPs) and heart failure, 2) redox biology and gain of ‘toxic’ function mechanisms in aggregation-prone diseases, and 3) stem and human iPSCs for cellular regeneration.

1) Alzheimer’s disease is a well-known protein misfolding disorder but few research scientists recognize that heart failure shares similar pathogenic mechanism(s). Our longstanding interests in the roles of small HSPs, which double as molecular chaperones, are focusing on what mechanisms govern the fate by which acquired (e.g., heart attacks) and/or inherited (e.g., hypertrophic cardiomyopathy) conditions lead to heart failure. Using transgenic and knockout mouse technology, this line of investigation might explain how chaperone-like functions of HSPs might ultimately be exploited therapeutically to speed the physiological recovery in tissues damaged after a heart attack.

2) Many results of numerous antioxidants in clinical trials have failed to show therapeutic benefits. We have recently discovered a new disease mechanism: “reductive stress” that challenges the existing paradigm of oxidative stress.  In transgenic mice recapitulating a protein-misfolding cardiomyopathy associated with myofibrillar disease in humans, we have demonstrated that decreasing the function of glucose-6-phosphate dehydrogenase (G6PD), an antioxidant that generates the reductant NADPH, “cures” the disease in mice by ameliorating reductive stress, aggressome formation, hypertrophy, heart failure and death. Ours collaborative studies in complementary model systems (e.g., flies, yeast, mice) are seeking to identify other disease-causing mutations and their potential interacting pathways that either increase resistance and/or decrease susceptibility in disease pathogenesis.

3) Development of human induced pluripotent stem cells (iPSCs) derived from adult somatic cells entirely circumvents usage of embryonic stem cells. We are testing the hypothesis that the pathogenic transition of cardiac and neurodegenerative diseases are causally related to dysregulation of stress response and anti-oxidative pathways, linked to macromolecular damage, in adult stem and progenitor cells. After recent sabbatical training at the Mass General Hospital/Harvard Stem Cell Institute and Gladstone Institute forCardiovascular Research/UCSF, Dr. Benjamin and colleagues are pursuing investigations 1) to understand redox-signaling mechanisms influencing cardiac  differentiation in human iPSC and 2) to model disease-specific iPSCs from patients with myofibrillar disease. To achieve the latter aim, we are seeking collaborators to establish an international consortium for modeling rare myofibrillar and related diseases using our iPSC platform technology.

   Laboratory Director

 

Ivor J. Benjamin, MD, FAHA, FACC Professor of Medicine and Biochemistry Christi T. Smith Endowed Chair for Cardiovascular Research ivor.benjamin@hsc.utah.edu

   Current Lab Members:

Alison Ausman Administrative Assistant alison.ausman@hsc.utah.edu	Elisabeth Christians, DVM, PhD Research Associate Professor elisabeth.christians@hsc.utah.edu	David Coe Lab Technician david.coe@hsc.utah.edu
Katie Mitzelfelt, PhD Student Graduate Student katie.A.Barber@utah.edu	Soumyajit Banerjee Mustafi, PhD Post Doctoral Research Associate soumyajit.mustafi@hsc.utah.edu	Greg Pratt  Sr Laboratory Specialist greg.pratt@hsc.utah.edu
Michael Riedel, PhD Post Doctoral Research Associate michael.riedel@utah.edu	Graydon Taylor, Undergrad Research Assistant graydon.taylor@hsc.utah.edu	Xiaohui Wang, MD, PhD Research Associate xiaohui.wang@hsc.utah.edu

Lab Alumni:

John Erikson, MD, PhD - Fellow from 1992-1994
Current activities: Program Director, Cardiovascular Disease Fellowship, UTHSC San Antonio, Texas

Lie Shao, MD - Lab member from 1993-1995
Current activities: Pathology Residency, John Hopkins Hospital, Maryland

Jacqueline Brown, PhD - Fellow from 1994-1996
Current activities: Teacher, San Angelo, Texas

D. Randy McMillan - Lab member from 1994-1998
Current activities: Assistant Professor, Department of Pediatrics, White Lab, UTSW

Xiao-Xia Zuo, MD - Lab member from 1996-1999
Current activities: Staff physician, Hunan Hospital, China

Xianzhong Xiao - Fellow from 1996-1999
Current activities: Professor of Pathophysiology, Dean of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

Bishop Curry - Fellow from 1996-1998
Current activities: Site Head, Executive Director of Comparative Medicine at Pfizer Pharmaceuticals. Site Head, Worldwide Comparative Medicine at Pfizer Pharmaceuticals. NCI-Animal Program Director / Animal Facility Operations and Veterinary Care at Science Applications International Corporation, Virginia

Alberta Davis - Fellow from 1997-1999
Current activities: Science writer, Alcon Pharmaceuticals

Li Liu - Medical student from 2000-2002
Current activities: Staff physician, Jiangso Medical University, Zhenjiang, China

Patrice Connell - Fellow from 2000-2003
Current activities:

Liang-Jun Yan - Fellow from 2000-2003
Current activities: Associate professor, University of Northern Texas Health Sciences Center

Sathya Srinivasan - Fellow from 2003-2005
Current activities: Staff scientist, University of Calgary, Alberta, Canada

Raj Sooroppan - Fellow from 2003-2006
Current activities: Research Assistant Professor, University of Utah School of Medicine

Ryan Taylor - Fellow from 2004-2007
Current activities: Medical Science Liasion, Actelion Pharmaceuticals US

Lensey Scott - Fellow from 2009-2011
Current activities: Research scientist, Mississippi State University

Takahiro Ishiwata, MD, PhD – Fellow  from 2010 – 2011
Current activities:
 
Joel Pieper – Research Assistant from 2010-2012
Current activities:
 
Takashi Kanai – Fellow from 2011-2012
Current activities: 

Huali Zhang – Fellow from 2011-2012 
Current activities: 

Qiang Lui – Research Assistant from 2010-2012 
Current activities: 

Pattraranee Limphong – Fellow from 2009-2012 
Current activities: 

 

Selected Publications:

• Limphong P, Zhang H, Liu Q, Christians E, Riedel M, Ivey K, Cheng P, Taylor G, Winge D, Srivastava D, Benjamin IJ. Modeling Protein Aggregation Cardiomyopathy using Murine Induced Pluripotent Stem Cells. Stem Cells Translational Medicine. (In revision)

• Brewer AC, Mustafi SB, Murray T, Benjamin IJ. Reductive Stress Linked to Small HSPs, G6PD and NRF2 Pathways in Heart Disease. [Review]. Antioxidants & Redox Signaling. (Submitted)

• Zhang H, Liu Q, Limphong P, Wende A, Wang X, Zhang X, Pratt GW, Schubert HL, Hill CP, Christians E, Benjamin IJ. Cataract-related Human CryAB Mutation Associated with Protein Aggregation Spares the Development of Desmin-related Cardiomyopathy in Mice. J Mol Cell Cardiol. (In Review)

• Heng B. Xie HB, Cammarato A, Suggs JA, Lin H-C, Bernstein SI, Benjamin IJ#, Golic KG#. NADPH Metabolic Network regulates human aB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster. #Corresponding authors. PLoS Genet. (In Review)

• Ishiwata T, Orosz, Wang X, Mustafi SB, Pratt GW, Christians ES, Boudina S, Able ED, Benjamin IJ. HSPB2 Is Dispensable for the Cardiac Hypertrophic Response But Reduces Mitochondrial Energetics Following Pressure Overload in Mice. PLoS ONE. 2012;7(8):e42118 Epub 2012 Aug 1.

• Kim G, Meriin A, Gabai V, Christians E, Benjamin IJ, Wilson A, Wolozin B, Sherman M. The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell. (In Press)

• Christians ES, Ishiwata T, Benjamin IJ. Small heat shock proteins in redox metabolism: Implications for cardiovascular diseases. Int J Biochem Cell Biol. 2012 Oct;44(10):1632-45. Epub 2012 Jun 15.

• Benjamin IJ. Targeting Endoglin, an Auxiliary TGF-beta Coreceptor, to Prevent Fibrosis and Heart Failure. Circulation.  Jun5;125(22): 2689-91. Epub 2012 May 16

• Zhang H, Ahn YH, Benjamin IJ, Honda T, Hicks RJ, Calabrese V, Cole PA, Dinkova-Kostova AT. HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway. Chem Biol, 18(11), 1355-61 

• Zhang H, Limphong P, Pieper J, Liu Q, Rodesch C, Christians E, Benjamin IJ. Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.  FASEB J (Online), 26(4), 1442-51. 

• Christians E, Benjamin IJ. Proteostasis and redox state in the heart. AJP Heart and Circulatory Physiology. Published online Oct. 13, 2011. 

• Sherman M, Gabai V, Meng L, Mills T, Benjamin IJ (In Press). Heat shock transcription factor Hsf1 affects tumor progression by regulating HIF-1 and RNA-binding protein HuR. Mol Cell Bio.

• Tamaru T, Hattori M, Honda K, Benjamin IJ, Ozawa T, Takamatsu K. Synchronization of Circadian Per2 Rhythms and HSF1-BMAL1:CLOCK Interaction in Mouse Fibroblasts after Short-Term Heat Shock Pulse. PLoS ONE. 2011;6(9):e24521. Epub 2011 Sep 7.

• Namakkal Soorappan R, Varadharaj S, Khanderao GD, Davidson CJ, Kannan S, Firpo MA, Zweier J, Benjamin IJ. Sustained Activation of Nrf2/ARE Signaling Promotes Reductive Stress in the Human Mutant Protein Aggregation Cardiomyopathy in Mice. Antioxid Redox Signal. 2011 Mar 15;14(6):957-71. Epub 2011 Feb 2.

• Zhang H, Rajasekaran NS, Orosz A, Xiao X, Rechsteiner M, Benjamin IJ. Selective degradation of aggregate-prone CryAB mutants by HSPB1 is mediated by ubiquitin-proteasome pathways. J Mol Cell Cardiol. 2010 Dec;49(6):918-30. Epub 2010 Sep 21.

• Zhang X, Min X, Li C, Benjamin IJ, Qian B, Zhang X, Ding Z, Gao X, Yao Y, Ma Y, Cheng Y, Liu L. Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension. 2010 Jun;55(6):1412-7. Epub 2010 May 3.

• Cooper ZA, Ghosh A, Gupta A, Maity T, Benjamin IJ, Vogel SN, Hasday JD, Singh IS. Febrile-range temperature modifies cytokine gene expression in LPS-stimulated macrophages by differentially modifying NF-{kappa}B recruitment to cytokine gene promoters.  Am J Physiol Cell Physiol. 2010 Jan;298(1):C171-81. Epub 2009 Oct 21.

• Ralser M, Benjamin IJ. Reductive stress on life span extension in C. elegans. BMC Research Notes 1:19, 2008.

• Rajasekaran NS, Firpo MA*, Connell P, Milash B, Weiss R, Benjamin IJ. Global Expression Profiling Identifies a Novel Biosignature for Protien aggregation R120GCryAB Cardiomyopathy in Mice. Physiological Genomics. 2008, Jul 15.

• Reinke H, Saini C, Fleury-Olela F, Dibner C, Benjamin IJ, Schibler U. Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor. Genes Dev, 22(3), 331-45, 2008.

• Pinz I, Robbins J, Rajasekaran NS, Benjamin IJ, Ingwall JS. (2007). Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPb2 using genetically modified mouse hearts. FASEB J, 22:84-92, 2008.

• Benjamin IJ, Guo Y, Srinivasan S, Boudina S, Taylor RP, Rajasekaran NS, Gottlieb R, Wawrousek EF, Abel ED, Bolli R. CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice. AJP-Heart Circ Physiol. 293: H3201-3209, 2007.

• Rajasekaran NS, Connell P, Christians ES, Yan L-J, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, Barry WH, Loscalzo J, Odelberg SJ, and Benjamin IJ. Human alphaB-Crystallin Mutation Causes Oxido-reductive Stress and Protein Aggregation Cardiomyopathy in Mice. Cell,130(3), 427-39, 2007.

• Corey LL, Weirich CS, Benjamin IJ, Kingston RE.  Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation.  Genes Dev Jun 1;17(11):1392-401, 2003.

• Yan L-J, Christians E, Liu L, Xiao X, Sohal S, and Benjamin IJ. Mouse Heat Shock Transcription Factor 1 Deficiency Alters Cardiac Redox Homeostasis and Increases Mitochondrial Oxidative Damage. EMBO J 21:5164-72, 2002.

• Christians E, Davis AD, Thomas S, and Benjamin IJ.  Embyonic Development: Maternal Effect of Hsf1 on Reproductive Success.  Nature, 407,(6805) 693-694, 2000.

• Xiao X, Davis AA, McMillan DR, Curry B, Richardson J, and Benjamin IJ. HSF1 is required for Extraembryonic Development, Postnatal Growth and Protection during Inflammatory Responses in Mice. EMBO J. Vol. 18: 5943‑5952, 1999

Association of Black Cardiologists award Dr. Ivor Benjamin the 2011 Dr. Daniel Savage Memorial Science Award

Dr. Benjamin was honored to receive the "2011 Dr. Daniel Savage Memorial Science Award" on October 29 from the Association of Black Cardiologists. Dr. Benjamin accepted the award at ABC's "Saving Hearts for Generations Dinner" in Washington, D.C. The award is ABC's highest honor, initiated in 1990 to recognize scientific achievement in the areas of cardiovascular disease and research. This annual award is named after Daniel D. Savage, M.D., PhD, who was heralded by his peers as the first to determine the role Left Ventricular Hypertrophy plays in cardiovascular disease.

Dr. Benjamin was awarded with the recognition of pioneering work in the areas of novel genetic pathways for cardioprotection; molecular and genetic analysis of heat shock transcription factors and their role in genetic development; and molecular mechanism of alpha B crystalline R1 20G familial cardiomyopathy.

Upcoming Events:

• Dr. Ivor J. Benjamin will be presenting as invited speaker at the University of Kentucky Deans Distinguished Speaker Series on October 5, 2012. Lexington, Kentucky, USA.

• Dr. Ivor J. Benjamin will be presenting as invited speaker at the University of South Alabama Distinguished Scientist Seminar on October 18, 2012. Mobile, Alabama, USA.

• Dr. Ivor J. Benjamin will be presenting as invited speaker at the The 2012 Cardioprotection Colloquium.  November 2, 2102.  Los Angeles, California, USA.

• Dr. Ivor J. Benjamin will be participating in the American Heart Association Scientific Sessions 2012. November 3-4. Los Angeles, California, USA.

• Dr. Ivor J. Benjamin will be participating in the National Heart, Lung, and Blood Institute (NHLBI) Protein Workshop on November 19 & 20, 2012. Bethsesda, Maryland, USA.

Prior Events:

• Dr. Ivor J. Benjamin presented a Plenary Lecture at the University of South Dakota Sanford School of Medicine - Second Annuyal Symposium on Ubiquitin, Protein Quality Control & Molecular Pathogenesis. "New Insights on the Myofibrillar Manifestations Caused by Human CryAP Mutants."  June 13-15, 2012, Deadwood, South Dakota, USA.

• Dr. Ivor Benjamin Hosted the Leducq Transatlantic Network Retreat 2012, an international scientific retreat for the Transatlantic Network of Excellence: Redox and nitrosative regulation of cardiac remodeling: novel therapeutic approaches for heart failure, funded by Fondation Leducq.  April 5-8, 2012, Kimball junction, Utah, USA.

• Dr. Ivor J. Benjamin presented at the Cell Stress Society International -IX Cell Strtess Society International Workshop on the Molecular Biology of Stress Response. "Redox Stress Response Pathways: A Balancing Act with Rhythmic Moves." May 27-30, 2012, Porto Alegre, Brazil.

• Dr. Ivor J. Benjamin presented at American Heart Assosication Scientific Sessions 2011. "Regulation of Cardiac Signaling Mechanisms by Reductive Stress." November 13, 2011, Orlando, Florida, USA.

• Dr. Ivor J. Benjamin presented at the North American Vascular Biology Organization - Workshops in Vascular Biology.  "Oxido-reductive Stress Signaling Networks in the Heart," October 16-20, 2011, Hyannis, Massachussetts, USA.

• Dr. Ivor J. Benjamin presented at the Seventh Annual NIH Director's Pioneer Award Symposium "Modeling Oxido-reductive Stress Networks and Protein Aggregation Diseases from Human to Mice and Flies (and back)." September 20-21, 2011, Bethesda, Maryland, USA.

• Dr. Ivor J. Benjamin presented at the Cell Stress Society International (CSSI)  Fifth International Congress on Stress Responses in Biology and Medicine . "Protein-induced diseases and Oxido-reductive Stress: Current concepts and Future Directions," August 22-25, 2011, Quebec City, Canada.

• Dr. Ivor J. Benjamin presented at the  Gordon Research Conferences  Stress Proteins in Growth, Development and Disease Conference. "Redox Signaling Networks Underlying Protein-induced Diseases in Flies and Mice".  July 17-22, 2011, Lucca, Italy.

• Dr. Ivor J. Benjamin presented at the University of South Dakota Sanford School of Medicine -  Inaugural Symposium on Ubiquitin, Protein Quality Control and Molecular Pathogenesis Symposium. "Chaperone-dependent Pathways and Protein Degradation." June 22-24, 2011, Vermillion, South Dakota, USA.

• Dr. Ivor J. Benjamin presented at the Stanford Cardiovascular Institute - Frontiers of Cardiovascular Science Seminar Series. "Modeling Oxido-reductive Stress Signaling Networks linked to Protein-induced Heart Disease in flies and mice," June 7, 2011, Palo Alto, California, USA.

• Dr. Ivor J. Benjamin presented at the Keystone Symposia on Molecular and Cellular Biology - Mechanisms of Cardiac Growth, Death and Regeneration (X3)Conference. "Mammalian HSP-HSF Regulatory Network For Protein Quality Control."  Feb 22 - 27, 2011, in Keystone Resort, Colorado, USA.

• Dr. Ivor J. Benjamin presented at the European Molecular Biology Organization (EMBO) Conference Series  - The Biology of Molecular Chaperones, Cellular Protein Homostasis in Disease and Ageing Conference.  "Chaperones in Normal and Aberrant Protein Folding, Aging & Cancer".  May 22-28, 2009, in Debrovnik,Croatia.

• Dr. Ivor J. Benjamin presented at the 49th Annual American Heart Association Scientific Conferences "The Leadership Role of the AHA and International Organizations and Future Directions Addressing the Global Burden of Cardiovascular Disease." March 10-12, 2009  in Palm Harbor, Florida, USA.

• Dr. Ivor J. Benjamin presented a talk about "Heart  Throbs and Beats in the New Era of Stem Cells" on , at the University of Utah for the Women Investing in Service and Health Organization (WISH). March 29, 2009, Salt Lake City, Utah, USA

• Read Dr. Ivor J. Benjamin's interview on how "Too much oxidant may lead to heart disease" by Lois M. Collins, Deseret News , Published Thursday, August 9, 2007, Salt Lake City, Utah, USA.

• Dr. Ivor J. Benjamin presented at the Gordon Research Conferences  Stress Proteins in Growth, Development and Disease. "New Biosignatures for Protein Aggregation Diseases." August 19-24, 2007, Magdalen College, Oxford, United Kingdom.

• Dr. Andras Orosz presented at the 2nd World Conferfence of Stress. "Dual Roles of Heat Shock Factor 1 (HSF1) in Cardioprotection, Pathologic Hypertrophy and Heart Failure in Transgenic Mice."  August 23-26, 2007, Budapest, Hungary.

Mailing Address:

Dr. Ivor J. Benjamin
University of Utah
Division of Cardiology
Room 4A100
30 North 1900 East
Salt Lake City, UT 84132

(801) 581-7715

Request Materials:

NOTICE: Shipment of materials will be billed to recipient

Please provide Emory account number for mice or Fed Ex for cells

Dr. Benjamin's Lab Manager is:

• Greg Pratt
  greg.pratt@hsc.utah.edu
  Phone:  801-581-6785
  Fax:  801-585-1082

Dr. Benjamin's administrative assistant is:

• Alison Ausman
  alison.ausman@hsc.utah.edu
  Phone:  801-587-9785
  Fax:  801-585-1082

Please provide the following information, which will be used to initiate an MTA

• Name of firm or institution requesting materials
• Recipient contact person name, address, phone, e-mail

Please provide the following information for mice:

• Institution requesting animals
• Department address, phone, e-mail
• Lab contact
• Animal resource contact person
• ARC phone, address for shipping, e-mail
• Veterinarian name
• Veterinarian phone, fax, e-mail

Health report will be faxed to the veterinarian of the receiving institution and any additional requirements will be discussed between institutions.

Fall 2012  All meetings to be held in the Renzetti Conference Room (Wintrobe Building, 7th floor South Corridor)

                                            September 2012

Wednesday September 19 - 9:00 AM:  Shayne Squires Presenting

Wednesday September 26 - 1:00 PM:  Soumyajit Mustafi Presenting - R120G (meeting via Google Web conference available)

October 2012

Wednesday October 10 - 9:00 AM:  Heng Xie Presenting - R120G

For general laboratory information:

Greg Pratt
Sr Laboratory Specialist & Lab Manager
Greg.Pratt@hsc.utah.edu
Phone:  801-581-6785
Fax:  801-585-1082

For general administrative inquiries:

Alison Ausman
Administrative Assistant to Dr. Ivor Benjamin
alison.ausman@hsc.utah.edu
Phone: 801-587-9785
Fax: 801-585-1082

EMPLOYMENT:

The Benjamin Lab currently has no open positions.

Our laboratory welcomes trainees at all levels (graduate students, medical students and postdoctoral clinical or basic research fellows) to join our multidisciplinary investigative team.

 Graduate and Postdoctoral Trainees: Please visit the University of Utah Bioscience program for more information on the Molecular Biology and Biological Chemistry Programs