Marriott Heart Disease Research Program

Rochester, MN, United States

Marriott Heart Disease Research Program

Rochester, MN, United States

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Arrell D.K.,Marriott Heart Disease Research Program | Arrell D.K.,Molecular Therapeutics | Arrell D.K.,Heart Genetics | Terzic A.,Marriott Heart Disease Research Program | And 2 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

Systems biology provides a platform for integrating multiple components and interactions underlying cell, organ, and organism processes in health and disease. Beyond traditional approaches focused on individual molecules or pathways, bioinformatic network analysis of high-throughput data sets offers an opportunity for integration of biological complexity and multilevel connectivity. Emerging applications in rational drug discovery range from targeting and modeling disease-corrupted networks to screening chemical or ligand libraries to identification/validation of drug-target interactions for improved efficacy and safety. © 2010 American Society for Clinical Pharmacology and Therapeutics.


Murthy V.,Molecular Therapeutics | Reyes S.,Marriott Heart Disease Research Program | Geng L.,Molecular Therapeutics | Gao Y.,Molecular Therapeutics | Brimijoin S.,Molecular Therapeutics
Journal of Pharmacology and Experimental Therapeutics | Year: 2016

Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.


Arrell D.K.,Marriott Heart Disease Research Program | Arrell D.K.,Mayo Medical School | Arrell D.K.,Molecular Therapeutics | Zlatkovic Lindor J.,Marriott Heart Disease Research Program | And 8 more authors.
Cardiovascular Research | Year: 2011

Systems biology provides an integrative platform by which to account for the biological complexity related to cardiac health and disease. In this way, consequences of ATP-sensitive K+ (KATP) channel deficiency for heart failure prediction, diagnosis, and therapy were resolved recently at a proteomic level. Under stress-free conditions, knockout of the Kir6.2 K ATP channel pore induced metabolic proteome remodelling, revealing overrepresentation of markers of cardiovascular disease. Imposed stress precipitated structural and functional defects in Kir6.2-knockout hearts, decreasing survival and validating prediction of disease susceptibility. In the setting of hypertension, a leading risk for heart failure development, proteomic analysis diagnosed the metabolism-centric impact of KATP channel deficiency in disease. Bioinformatic interrogation of KATP channel-dependent proteome prioritized heart-specific adverse effects, exposing cardiomyopathic traits of aggravated contractility, fibrosis, and ventricular hypertrophy. In dilated cardiomyopathy induced by Kir6.2-knockout pressure overload, proteomic remodelling was exacerbated, underlying a multifaceted molecular pathology that indicates the necessity for a broad-based strategy to achieve repair. Embryonic stem cell intervention in cardiomyopathic K ATP channel knockout hearts elicited a distinct proteome signature that forecast amelioration of adverse cardiac outcomes. Functional/structural measurements validated improved contractile performance, reduced ventricular size, and decreased cardiac damage in the treated cohort, while systems assessment unmasked cardiovascular development as a prioritized biological function in stem cell-reconstructed hearts. Thus, proteomic deconvolution of KATP channel-deficient hearts provides definitive evidence for the channels homeostatic contribution to the cardiac metaboproteome and establishes the utility of systems-oriented approaches to predict disease susceptibility, diagnose consequences of heart failure progression, and monitor therapy outcome. © 2010 The Author.


Behfar A.,Marriott Heart Disease Research Program | Yamada S.,Marriott Heart Disease Research Program | Crespo-Diaz R.,Marriott Heart Disease Research Program | Nesbitt J.J.,Marriott Heart Disease Research Program | And 7 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction. Background: Adult stem cells, delivered in their nave state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods: hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. Results: Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helixloophelix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Conclusions: Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy. © 2010 American College of Cardiology Foundation.


Nelson T.J.,Marriott Heart Disease Research Program | Martinez-Fernandez A.,Marriott Heart Disease Research Program | Terzic A.,Marriott Heart Disease Research Program
Nature Reviews Cardiology | Year: 2010

Nuclear reprogramming of somatic cells with ectopic stemness factors to bioengineer pluripotent autologous stem cells signals a new era in regenerative medicine. The study of developmental biology has provided a roadmap for cardiac differentiation from embryonic tissue formation to adult heart muscle rejuvenation. Understanding the molecular mechanisms of stem-cell-derived cardiogenesis enables the reproducible generation, isolation, and monitoring of progenitors that have the capacity to recapitulate embryogenesis and differentiate into mature cardiac tissue. With the advent of induced pluripotent stem (iPS) cell technology, patient-specific stem cells provide a reference point to systematically decipher cardiogenic differentiation through discrete stages of development. Interrogation of iPS cells and their progeny from selected cohorts of patients is an innovative approach towards uncovering the molecular mechanisms of disease. Thus, the principles of cardiogenesis can now be applied to regenerative medicine in order to optimize personalized therapeutics, diagnostics, and discovery-based science for the development of novel clinical applications. © 2010 Macmillan Publishers Limited. All rights reserved.


Olson T.M.,Marriott Heart Disease Research Program | Olson T.M.,Mayo Medical School | Terzic A.,Marriott Heart Disease Research Program
Pflugers Archiv European Journal of Physiology | Year: 2010

Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATPsensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potentialdependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in K ATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, K ATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-atlarge and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within K ATP channel genes and the spectrum of genotype-phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy. © The Author(s) 2009.


Nelson T.J.,Marriott Heart Disease Research Program | Martinez-Fernandez A.,Marriott Heart Disease Research Program | Yamada S.,Marriott Heart Disease Research Program | Ikeda Y.,Mayo Medical School | And 2 more authors.
Stem Cells and Cloning: Advances and Applications | Year: 2010

Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson's disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms. © 2010 Nelson et al, publisher and licensee Dove Medical Press Ltd.


Terzic A.,Marriott Heart Disease Research Program | Alekseev A.E.,Marriott Heart Disease Research Program | Yamada S.,Marriott Heart Disease Research Program | Reyes S.,Marriott Heart Disease Research Program | And 2 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2011

Deficient cellular energetics set by aberrant KATP channel function increasingly is implicated in a spectrum of conditions underlying metabolic imbalance and electric instability.5 Indeed, cardiac K ATP channelopathies are emerging as a recognized disease entity underlying heart failure and arrhythmia. 19 Understanding the molecular structure and function of KATP channel subunits, 8 and their relationship to cellular metabolic signaling, 99 has been instrumental in interpreting the pathophysiology of channel malfunction associated with heart disease predisposition (Figure 3).12 From individual patients to populations, variants in K ATP channel genes now have been documented in human dilated cardiomyopathy21 and atrial fibrillation20 and as risk factors for electric instability,93,94 adverse cardiac remodeling,23 impaired performance under stress,22 or myocardial infarction.98 Beyond the initial deciphering of genotype-phenotype relationships, development and application of high-throughput platforms to screen for disrupted coding and regulatory sequences in cardioprotective KATP channel genes as well as diagnosis of corrupted interactions within the cellular milieu would advance current knowledge regarding this homeostatic channel complex and its implications in cardiovascular medicine. In particular, deconvolution of altered metabolic pathways and signaling cascades associated with pathogenic KATP channel mutation may offer unique opportunities to pinpoint lesions that stratify the consequences of genetic variation on disease traits.18 In this regard, it can be anticipated that systems biology and network medicine strategies increasingly will be deployed to resolve the KATP channel interactome.11 Mapping of the systems integration of molecules and their respective biological networks in health versus disease will, in turn, guide the judicious development of prognostic discriminators of disease variability and selection of treatment response predictors.100-102 Advances in the molecular medicine of KATP channelopathies thus are poised to offer new perspectives in the diagnosis and therapy of individuals and populations.103-107. © 2011 American Heart Association, Inc.


Folmes C.D.L.,Marriott Heart Disease Research Program | Kent Arrell D.,Marriott Heart Disease Research Program | Zlatkovic-Lindor J.,Marriott Heart Disease Research Program | Martinez-Fernandez A.,Marriott Heart Disease Research Program | And 3 more authors.
Cell Cycle | Year: 2013

Nuclear reprogramming resets differentiated tissue to generate induced pluripotent stem (iPS) cells. While genomic attributes underlying reacquisition of the embryonic-like state have been delineated, less is known regarding the metabolic dynamics underscoring induction of pluripotency. Metabolomic profiling of fibroblasts vs. iPS cells demonstrated nuclear reprogramming-associated induction of glycolysis, realized through augmented utilization of glucose and accumulation of lactate. Real-time assessment unmasked downregulated mitochondrial reserve capacity and ATP turnover correlating with pluripotent induction. Reduction in oxygen consumption and acceleration of extracellular acidification rates represent high-throughput markers of the transition from oxidative to glycolytic metabolism, characterizing stemness acquisition. The bioenergetic transition was supported by proteome remodeling, whereby 441 proteins were altered between fibroblasts and derived iPS cells. Systems analysis revealed overrepresented canonical pathways and interactome-associated biological processes predicting differential metabolic behavior in response to reprogramming stimuli, including upregulation of glycolysis, purine, arginine, proline, ribonucleoside and ribonucleotide metabolism, and biopolymer and macromolecular catabolism, with concomitant downregulation of oxidative phosphorylation, phosphate metabolism regulation, and precursor biosynthesis processes, prioritizing the impact of energy metabolism within the hierarchy of nuclear reprogramming. Thus, metabolome and metaboproteome remodeling is integral for induction of pluripotency, expanding on the genetic and epigenetic requirements for cell fate manipulation. © 2013 Landes Bioscience.


Thatava T.,Rochester College | Kudva Y.C.,Rochester College | Edukulla R.,Rochester College | Squillace K.,Rochester College | And 7 more authors.
Molecular Therapy | Year: 2013

Nuclear reprogramming of adult somatic tissue enables embryo-independent generation of autologous, patient-specific induced pluripotent stem (iPS) cells. Exploiting this emergent regenerative platform for individualized medicine applications requires the establishment of bioequivalence criteria across derived pluripotent lines and lineage-specified derivatives. Here, from individual patients with type 1 diabetes (T1D) multiple human iPS clones were produced and prospectively screened using a battery of developmental markers to assess respective differentiation propensity and proficiency in yielding functional insulin (INS)-producing progeny. Global gene expression profiles, pluripotency expression patterns, and the capacity to differentiate into SOX17-and FOXA2-positive definitive endoderm (DE)-like cells were comparable among individual iPS clones. However, notable intrapatient variation was evident upon further guided differentiation into HNF4α-and HNF1β-expressing primitive gut tube, and INS-and glucagon (GCG)-expressing islet-like cells. Differential dynamics of pluripotency-associated genes and pancreatic lineage-specifying genes underlined clonal variance. Successful generation of glucose-responsive INS-producing cells required silencing of stemness programs as well as the induction of stage-specific pancreatic transcription factors. Thus, comprehensive fingerprinting of individual clones is mandatory to secure homogenous pools amenable for diagnostic and therapeutic applications of iPS cells from patients with T1D. © The American Society of Gene & Cell Therapy.

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