2009-2010 LHI Lecture Recordings

 LHI Lecture
"Transcriptional regulation of cardiac morphogenesis"
Daniel J. Gary, MD, PhD
Professor of Medicine and St. Jude Medical Endowed Chair in Cardiology
Director, Lillehei Heart Institute
Chief, Cardiovascular Division
University of Minnesota Medical School
» more info about Dr. Garry from the Cardiovascular Division web site

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 LHI Lecture
“The Regulation of Central Angiotensin Receptor Expression in Heart Failure and its Role in Sympatho-Excitation”
Irving H. Zucker, Ph.D.
Theodore F. Hubbard Professor of Cardiovascular Research
Chairman, Department of Cellular & Integrative Physiology
University of Nebraska Medical Center
» more info about Dr. Zucker from the Cardiovascular Division web site

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Abstract:
A variety of peripheral and central mechanisms contribute to the progressive deterioration of cardiovascular regulation in the setting of chronic heart failure (CHF). Increased sympathetic outflow increases myocardial oxygen consumption, peripheral resistance and activates the renin-angiotensin system. It is important to understand the molecular and cellular mechanisms that are responsible for the sympatho-excitatory process in CHF. This seminar will focus on studies designed to understand the roles of Angiotensin II (Ang II), angiotensin receptors, and reactive oxidant stress on sympathetic activation in animal models of CHF. The data presented willdemonstrate that CHF is accompanied by an increase in Ang II in the central nervous system along with a significant up regulation of the Angiotensin Type 1 receptor (AT₁R), a decrease in the AT₂R. Furthermore, Angiotensin Converting Enzyme (ACE) is increased while its catabolic homologue, ACE₂ is decreased in areas of the medulla that regulate sympathetic outflow. The increase in AT₁R expression is mediated by activation of at least two transcription factors, Activator Protein-1 (AP-1) and Nuclear Factor Kappa B (NF_ΚB). The up regulation of AT₁R expression is dependent on Ang II binding thus initiating a positive feedback system further increasing sympathetic outflow. Activation of the AT₁R initiates an NADPH oxidase dependent increase in superoxide anion. Superoxide reduces the bioavailability of nitric oxide and thereby promotes the formation of peroxynitrite which nitrosylates a variety of proteins that regulate ion channel function. Superoxide also activates transcription factors that are involved with the regulation of Ang II receptor expression. All of the above processes contribute to a process of sympatho-excitation in CHF that promotes a downward spiral of cardiovascular deterioration.

 LHI Lecture
“Designing the Molecular Switch to Heart Performance”
Joseph M. Metzger, PhD
Professor & Chair, Dept. of Integrative Biology & Physiology
Maurice B. Visscher Endowed Chair in Physiology
University of Minnesota Medical School
» more info about Dr. Metzger from the Integrative Biology & Physiology web site

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 LHI Lecture
“The Regulation of Central Angiotensin Receptor Expression in Heart Failure and its Role in Sympatho-Excitation”
Vivian J. Bardwell, Ph.D.
Associate Professor
Department of Genetics, Cell Biology and Development/Cancer Center
University of Minnesota Medical School
» more info about Dr. Bardwell from the GCBD web site

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Abstract:
The transcriptional corepressor BCOR regulates gene expression in association with a complex of proteins capable of epigenetic chromatin modification. Mutations in human BCOR result in the X-linked Oculofaciocardiodental (OFCD) syndrome that involves developmental defects in multiple systems, including the ocular, skeletal, and cardiovascular systems. To determine the role of Bcor in mouse development, we have generated Bcor loss-of-function alleles in embryonic stem (ES) cells and in mice. In vitro differentiation of ES cells harboring Bcor loss-of-function alleles demonstrated a role for Bcor in the regulation of gene expression very early in ES cell differentiation into ectoderm, mesoderm, and downstream hematopoietic lineages. To unravel Bcor’s complex role during early embryogenesis and specifically in cardiovascular development, we are currently generating ubiquitous and cardiac-specific Bcor knockout mice. Initial findings reveal that ubiquitous Bcor inactivation in mice results in male lethality prior to embryonic turning and late gestation lethality of heterozygous females. Meanwhile, Bcor inactivation in males in the neural crest cell lineage results in perinatal lethality possibly due to observed cardiovascular defects.

 LHI Lecture
Double Trouble: RNA and Protein Gain of Function Effects in Spinocerebellar Ataxia Type 8 (SCA8)
Laura P. W. Ranum, Ph.D.
Professor of Genetics, Cell Biology and Development
Research Director, Paul and Sheila Wellstone Muscular Dystrophy Center
Institute of Human Genetics, University of Minnesota
» more info about Dr. Ranum from the IHG web site

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Abstract:
     Microsatellite expansions cause a number of dominantly-inherited neurological diseases including myotonic dystrophy (DM1 and DM2), Huntington's disease (HD and HDL2) and several forms of spinocerebellar ataxia (SCA). Expansions located in coding-regions cause dominant protein gain-of-function effects and non-coding expansions (DM and DM2) produce toxic RNA gain-of-function effects that in muscle have been shown to alter RNA splicing activities of MBNL and CELF proteins. We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8). Because the SCA8 expansion is transcribed, alternatively spliced, and polyadenylated in the CTG orientation we initially proposed that SCA8 is caused by an RNA gain-of-function mechanism similar to myotonic dystrophy. To elucidate the molecular events that cause SCA8, we developed a BAC transgenic mouse model in which the full length human SCA8 gene is expressed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype and a loss of cerebellar cortical inhibition. Surprisingly, we found 1C2-intranuclear inclusions in Purkinje cells in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a nearly pure polyglutamine protein encoded on a previously unidentified anti-parallel transcript spanning the repeat in the CAG direction. The neurological phenotype found in the SCA8 BAC expansion lines but not BAC control lines demonstrates the pathogenicity of the (CTG•CAG)n expansion.
     We now present three lines of evidence that SCA8 CUGexp transcripts cause RNA gain of function effects in the CNS. First, we demonstrate SCA8 CUGexp transcripts form ribonuclear inclusions that co-localize with MBNL1. Second, we show that genetic loss of Mbnl1 enhances motor coordination deficits in SCA8 mice. Third we show the GABA-A transporter-4 (Gabt4) gene, which is dramatically upregulated in SCA8, is a misregulated MBNL/CELF splicing target. These data demonstrate for the first time that CUGexp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUGexp disorders (DM, HDL2). While functional evidence for RNA gain-of-function effects is presented here, the additional discovery of intranuclear polyglutamine inclusions in SCA8 suggests disease pathogenesis is mediated by toxic gain-of-function mechanisms at both the protein and RNA levels. Additionally, the growing number of bidirectionally-expressed genes in the genome suggests unrecognized CUGexp RNAs contribute to some of the polyglutamine CAG•CTG disorders.

 LHI Lecture
“Chronic Administration of Poloxamer 188 Prevents Cardiac Injury and Ventricular Remodeling in Dystrophic Dogs”
De Wayne Townsend, DVM, PhD
Assistant Professor, Department of Integrative Biology and Physiology
University of Minnesota Medical School

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Abstract:
Background: Duchenne muscular dystrophy (DMD) is a fatal disease resulting from the loss of the cytoskeletal protein dystrophin and consequent damage to both skeletal and cardiac muscle cells. In the absence of dystrophin small tears in the cardiac sarcolemma arise causing loss of membrane integrity, muscle wasting, and eventual heart failure in DMD patients. There are no reports of long-term efficacious treatments for dystrophic cardiomyopathy. Hypothesis: The long term application of the chemical-based membrane sealant Poloxamer 188 (P188) will be safe and effectively slow the development of dystrophic cardiomyopathy. Methods/Results: Here we show chronic administration of P188 to dystrophin-deficient golden retriever muscular dystrophy (GRMD) dogs in vivo is both safe and effective in blocking the development of cardiac disease. Intravenous administration of 60 mg/kg/hour P188 for 8 weeks in adult GRMD dogs prevented the onset of heart disease observed in saline infused animals. Specifically, significant reductions in fibrotic lesions were observed in P188 infusion (5.8 ±0.9% of total myocardium) compared to saline infused controls (11.0±1.1%). In saline infused dogs elevations of serum cTnI and BNP were observed. These elevations were not present in P188 infused dogs, indicating a reduction in both myocardial necrosis and congestion in P188 infused dogs. Treatment with P188 also prevented left ventricular dilation that was evident in untreated GRMD control dogs (diastolic volumes: 39±4 vs. 24±3 ml for saline and P188 infused dogs respectively). Regardless of treatment, adult cardiac myocytes isolated from either P188 or saline infused GRMD dogs revealed significantly abnormal passive tension-extension properties. These functional deficits of the isolated myocyte were rapidly reversed upon addition of P188. Conclusion: Given the clinical prominence of cardiomyopathy and heart failure in DMD, there is an urgent need for effective therapies for the dystrophic heart. This study demonstrates that P188 has the promise of an immediately available therapeutic approach for mitigating the progression of cardiac disease in DMD.

 LHI Lecture
New ways to make pancreatic beta cells
Jonathan MW Slack, PhD, FMedSci
Director, Stem Cell Institute
Tulloch Chair of Stem Cell Biology
University of Minnesota
» more info about Dr. Slack from the SCI web site

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Abstract:
Islet transplantation is an effective method of cell therapy but the supply of cells is seriously inadequate. There are various novel approaches aimed at obtaining more beta cells. One of these is the reprogramming of other cell types by overexpression of selected developmental transcription factors. Results will be presented using hepatocytes and biliary epithelial cells as the target cell types. 

 LHI Lecture
“Pim-1 kinase revealed: a new chapter in myocardial survival and regenerative signaling”
Mark Sussman, PhD
Biology Professor and Chief Research Scientist
San Diego State University Heart Institute
»more info about Dr. Sussman from the SDSU website

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Abstract:
Over the past decade a concerted effort by scientists and clinicians has advanced the use of gene therapy as an approach to treatment of heart failure. These studies have shown that genetic reprogramming of the myocardium can be used to prevent cell death, inhibit maladaptive remodeling, enhance hemodynamic function, promote angiogenesis, and block deleterious signaling. Although gene therapy approaches remain a popular avenue for delineating the role of proteins in cardiac repair and rescue, many practical aspects of gene therapy such as delivery and targeted expression in the myocardium, regulation of gene expression, and persistence of expression have hampered implementation of myocardial gene therapy for treatment of heart failure. However, recent discoveries related to regeneration and repair of the myocardium using stem cells have shifted the paradigm of treatment for myocardial disease. Discoveries linking stem cell-based therapies to improvements in myocardial performance have invigorated the field, but current limitations in stem cell-based approaches present significant barriers. This presentation will concentrate upon existing challenges in stem-cell based treatment and how these may be overcome by incorporation of gene therapy, resulting in a combinatorial approach that uses genetic engineering to potentiate stem cell activity for myocardial repair.

 LHI Lecture
“Nitric oxide: sex, death, and cardiovascular therapeutics”
Thomas Michel, MD, PhD
Co-Director, Leder Program in Human Biology
Translational Professor of Medicine (Biochemistry)
Federman Chair in Medical Education
Dean for Education
Harvard Medical School / Brigham and Women's Hospital
» more info about Dr. Michel from the Harvard web site

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sponsored in part by: Actelion Pharmaceuticals, Ltd.

Learning Objectives:
1. To understand the relationship between organic nitrate vasodilator drugs and endogenous pathways of NO metabolism.
2. To understand the effects of oxidative stress on nitric oxide signaling.
3. To understand key molecular mechanisms of endothelial dysfunction.

 LHI Lecture
“Large recombinant proteins as tools to understand and treat muscular dystrophy”
James M. Ervasti, PhD
Professor
Biochemistry, Molecular Biology and Biophysics
University of Minnesota
» more info about Dr. Ervasti from the BMBB web site

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Abstract:
While the absence of the large but low abundance protein dystrophin leads to Duchenne muscular dystrophy and some forms of human dilated cardiomyopathy, its function in striated muscle is not yet fully understood. My lab has uniquely established methods to express and purify full-length dystrophin and its close relative utrophin. Recently, we have: 1) identified a new pathological mechanism of disease for one group of patients with dystrophinopathy, 2) defined a new function for dystrophin, and 3) established proof-of-concept for a novel protein-replacement therapy for Duchenne muscular dystrophy. The seminar will therefore focus on the value of large recombinant proteins as tools for discovery in both basic and translational research.

 LHI Lecture
"Calcium Signaling Circuits as Therapeutic Modalities in Heart Failure"
Evangelia G. Kranias, PhD
Distinguished University Research Professor and Director, Cardiovascular Biology
Chairman, Department of Pharmacology & Cell Biophysics
University of Cincinnati
» more info about Dr. Kranias from the UC web site

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Abstract:
A clinical hallmark of human and experimental heart failure is impaired sarcoplasmic reticulum (SR) Ca2+ cycling, leading to depressed Ca-homeostasis and function. The SR is an intracellular membrane system that regulates contraction and relaxation of the heart. SR Ca-transport is mediated by the Ca2+-ATPase and its reversible regulator phospholamban (PLN); Ca is stored in the SR lumen by calsequestrin and the histidine rich Ca-binding protein (HRC); and Ca is released through the ryanodine receptor (RyR), which is regulated by junctin and triadin. The functional role of each of these key Ca-regulatory players has been elucidated by the generation and characterization of genetically altered mouse models. These studies indicate that targeting the activity of specific SR Ca-proteins may hold therapeutic promise in heart failure. Furthermore, human mutations have been identified in the SR Ca-cycling genes, which may serve as prognostic or diagnostic indicators for arrhythmias and heart failure.

 LHI Lecture
“Biophysics of Heart Failure”
David D. Thomas, PhD
Dietrich Professor of Structural Biology
Dept. of Biochemistry, Molecular Biology and Biophysics
University of Minnesota
» more info about Dr. Thomas from the BMBB web site

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Abstract:
My lab explores the fundamental molecular biophysics of muscle, asking questions like the following:

• How do muscle proteins move? Interact?
• How does this affect muscle contraction and regulation?
• What are the coolest toys you can get to study this stuff?

So we published a series of papers showing how to detect protein-protein interactions directly, using spectroscopic probes, lasers, magnets, and other gizmos. Some of these interactions (e.g., between phospholamban and the cardiac calcium pump) turn out to play a central role in heart failure. A few years ago, a biotech company scientist read our papers and realized that our methods could be applicable to designing therapy for heart failure. So they hired my lab, and it turns out they might be right.

I will discuss the resulting research on the use of biophysical spectroscopy for (a) high-throughput screening for drug discovery and (b) structure-based design of gene therapy.

 LHI Lecture
“Biased Signaling by G protein-Coupled Receptors”
Howard A. Rockman, MD
Chief, Division of Cardiology
Duke University Medical Center
» more info about Dr. Rockman from the Duke web site

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Learning Objectives:
1) Understand the new concept of Biased Signaling by GPCRs
2) Understand the role for beta-arrestin in G proteinindependent signaling
3) Understand the potential role of ligand bias in therapy for heart failure

 LHI Lecture
“Reprogramming cell fate with transcription factors”
Michael Kyba, PhD
Assistant Professor of Medicine
Lillehei Endowed Scholar
Department of Pediatrics and Lillehei Heart Institute
University of Minnesota
» more info about Dr. Kyba

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Abstract:
How different cells acquire their unique identities and how these identities are maintained is a central question in developmental biology. Several classical examples demonstrate that cell fate is malleable, in some cases altered simply by changing the environment of the cell, or by exposing a nucleus to a different cytoplasmic environment through cell fusion. More recent molecular studies have revealed that transcriptional regulation is central to acquisition and maintenance of cell fate. This emerging knowledge has opened the way for radical intervention in the cellular fate determination and maintenance systems, exemplified by the discovery of iPS cell reprogramming using ES cell-specific transcription factors. In this presentation, we demonstrate recently-discovered examples of lineage-specific cell fate changes accomplished by transient expression of specific transcription factors.

 LHI Lecture
Redefining Human Myocardial Biology
Piero Anversa, MD
Lecturer on Anaesthesia
Harvard Medical School / Brigham and Women's Hospital
» more info about Dr. Anversa from the Harvard web site

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Learning Objective:
To acquire a better understanding of the plasticity of the human heart.

 LHI Lecture
“Mechanisms guiding heart regeneration in zebrafish”
Kenneth D. Poss, PhD
Associate Professor, Cell Biology
Cell and Molecular Biology Program and Program in Genetics
Duke University
» more info about Dr. Poss from the Duke web site

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Abstract:
By contrast with mammals, teleost zebrafish regenerate cardiac muscle after major injury. Following resection of the apex of the zebrafish ventricle, cardiomyocyte hyperplasia renews myocardium and restricts scar formation.Very little is known about the mechanisms of heart regeneration, including whether an undifferentiated progenitor cell type is involved. Recently, we have used transgenic zebrafish strains and molecular markers to examine the origin of new myocardium during heart regeneration. Using similar approaches, we have also begun to investigate contributions to regeneration by non-myocardial tissues. Our findings identify dynamic cellular and molecular injury responses necessary to regenerate the zebrafish heart.

 LHI Lecture
“Therapeutic Potential of Hematopoietic and Vascular Cells Derived from Human Pluripotent Stem Cells”
Dan S. Kaufman, MD, PhD
Associate Professor of Medicine
Associate Director, Stem Cell Institute
University of Minnesota
» more info about Dr. Kaufman from the MICaB web site

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Abstract:
Human pluripotent stem cells consist of both human embryonic stem cells (hESCs) and the more recently described induced pluripotent stem cells (iPSCs). While both populations of cells have been touted as a novel starting point for new regenerative medicine therapies, better understanding of the developmental regulation and therapeutic potential of these cells is needed. Our lab has focused on derivation of hematopoietic cells and related mesodermal lineages from hESCs and iPSCs. While it is possible to effectively produce diverse mature blood cell populations, isolation and characterization of cells capable of long-term multilineage engraftment in vivo remains challenging, for reasons that will be discussed. However, we have been able to derive natural killer cells with potent anti-tumor activity. Additionally, we have more recently focused on derivation of endothelial and other vascular cells from hESCs and iPSCs with promising activity when tested with in vivo ischemia models.

 LHI Lecture
“Improving Management and Treatment of Duchenne Muscular Dystrophy”
John W. Day, MD, PhD
Professor of Neurology, Pediatrics, and Genetics, Cell Biology and Development
Institutes of Human Genetics and Translational Neuroscience
Director, Paul and Sheila Wellstone Muscular Dystrophy Center
University of Minnesota
» more info about Dr. Day from the Dept. of Neurology web site

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Abstract:
Duchenne Muscular dystrophy (DMD), the most common form of muscular dystrophy in childhood, cannot be eradicated by genetic counseling or pre-implantation testing alone because sporadic mutations are common in the causative gene, dystrophin, the largest gene in the human genome. Dystrophin is an essential sarcolemmal protein, so the resulting protein deficiency in this X-linked recessive disorder decreases membrane integrity and alterfunction of cell-surface proteins in skeletal and cardiac muscle.

Optimal management of DMD, focusing on secondary abnormalities that contribute to functional deterioration including muscle inflammation, inappropriate exercise and nutrition, inadequate ventilation and heart failure, can currently help young men with DMD live into their 30s. Novel treatments are now also proving fruitful, restoring the dystrophin protein by genetic, cell-based, protein-based or small molecule methods. There is reason to hope that meaningful approaches will help stop this fatal disease in the current generation of patients.

 LHI Lecture
“Emerging Stem Cell Platforms for Heart Repair”
Andre Terzic, MD, PhD
Marriott Family Endowed Chair of Cardiovascular Research
Professor of Medicine and Pharmacology, Medical Genetics
Director, Marriott Heart Disease Research Program
Director, NIH Training Program in "Cardiovasology"
Chair, Mayo Clinic Regenerative Medicine Task Force
Mayo Clinic Associate Director for Research
Co-Director, Mayo Clinic Center for Individualized Medicine
Mayo Clinic, Rochester, MN
» more info about Dr. Terzic from the Mayo Clinic web site

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Abstract:
A spectrum of natural stem cell sources, ranging from embryonic to adult progenitors, has been identified with unique potentials for tissue repair. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the overarching goal of cardiovascular regenerative medicine is to translate stem cell platforms into practice and achieve cures for diseases limited to palliative interventions. Harnessing the full potential of each platform will optimize matching stem cell-based biologics with the disease-specific niche environment of individual patients to maximize long-term management. Emerging discovery science with feedback from clinical translation is poised to transform medicine offering safe and effective stem cell biotherapeutics to enable personalized solutions for each patient.

 LHI Lecture
“Hematopoietic cell transplantation for correction of extracellular matrix disorder, recessive dystrophic epidermolysis bullosa”
Jakub Tolar, MD
Assistant Professor
Department of Pediatrics, Blood and Marrow Transplantation
University of Minnesota
» more info about Dr. Tolar from the Peds BMT web site

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Learning Objectives:
1. To introduce a concept of cross-correction and functional complementation.
2. To present data on cellular therapy of lethal extracellular matrix disorder, epidermolysis bullosa.
3. To discuss the impact of this novel paradigm on the field of cellular therapy for lethal non-malignant diseases.

 LHI Lecture
“Cardiovascular development from human pluripotent stem cells”
Gordon M. Keller, PhD
Director, McEwen Centre for Regenerative Medicine
Senior Scientist, Division of Stem Cell and Developmental Biology
Ontario Cancer Institute (OCI)
» more info about Dr. Keller from the McEwen Clinic web site

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Abstract:
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 LHI Lecture
“Regulation of Tissue Vascularization by Hypoxia-Inducible Factor 1”
Gregg L. Semenza, MD, PhD
Founding Director, Vascular Program
Institute for Cell Engineering;
C. Michael Armstrong Professor
Department of Pediatrics (in Genetic Medicine);
The Johns Hopkins University School of Medicine, Baltimore MD
» more info about Dr. Semenza from the Johns Hopkins web site

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 LHI Lecture
“MEF2-dependent gene regulatory networks in cardiac and skeletal muscle”
Francisco J. Naya, PhD
Assistant Professor of Biology
Program in Cell and Molecular Biology
Boston University
» more info about Dr. Naya from the Boston U web site

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Abstract:
The MEF2 family of transcription factors plays an important role in muscle differentiation but the specific gene programs regulated by each member have not been completely elucidated. While all MEF2 factors display similar transactivation properties in vitro, loss-of-function studies in mice have revealed remarkably different phenotypes. Our lab has focused on the molecular characterization of MEF2A knockout mice which display severe myofibrillar defects in cardiac muscle. Through a comprehensive expression analysis of cytoarchitectural genes in MEF2A-deficient hearts we have identified a cohort of misregulated genes whose products localize to the muscle costamere. The costamere is a specialized, macromolecular complex that links the Z-disc of peripheral myofibrils with the sarcolemma. Mutations in many costamere genes have been implicated in muscle disorders leading to sarcolemmal fragility and myofiber degeneration. Our findings indicate for the first time a role for MEF2A in the modulation of costamere integrity by directly regulating the expression of genes that function within this critical subcellular structure. Additionally, we have investigated the role of MEF2A in skeletal muscle differentiation. RNA interference-mediated knockdown of MEF2A in cultured muscle cells resulted in impaired muscle differentiation. Analysis of gene expression profiles in MEF2A knockdown cells points to a possible defect in myoblast cell proliferation. These studies were complemented by examining the role of MEF2A in muscle regeneration, a process which involves myoblast proliferation and fusion to generate new myofibers. Although skeletal muscle in MEF2A knockout mice appears normal, muscle regeneration was severely compromised, highlighted by a preponderance of necrotic myofibers, in response to cardiotoxin-induced muscle injury. Collectively, these studies provide mechanistic insight into the role of MEF2A as an essential regulator of specialized gene programs in cardiac and skeletal muscle.

 LHI Lecture
“MicroRNA regulatory networks in bone and muscle tumors”
Subree Subramanian, MSc, PhD
Assistant Professor
Laboratory Medicine and Pathology
University of Minnesota
» more info about Dr. Subramanian from his lab web site

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Abstract:
miRNAs are evolutionarily conserved, small, non-coding RNA molecules, 18-22 nucleotides in length that can control gene function through mRNA degradation, translation inhibition or chromatin-based silencing mechanisms. Each miRNA can potentially regulate hundreds of targets either directly or indirectly. Differential expression of miRNA between tumors and normal tissue has been described in many types of tumors. This seminar will cover the miRNA regulatory networks in bone-, muscle- and nerve sheath tumors.

 LHI Lecture
“Stress and the Heart: an Unfolding Story”
Jeffrey Robbins, PhD
Professor of Pediatrics and Adjunct Professor of Molecular Physiology
University of Cincinnati College of Medicine
» more info about Dr. Robbins from the UC web site

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Learning Objectives:
At the end of this lecture, the listeners should be able to:
1. Understand aspects of the cardiac stress response in the myocardium
2. Appreciate the role that molecular chaperones play in normal cardiac function
3. Clearly understand that the stress response is a general pathway that is important to cardiac disease
4. Appreciate the role that intra-cellular pre-amyloids oligomers play in heart disease.
»download full abstract

 LHI Lecture
“Regulation of Multiple Cell Signaling Pathways by Proteoglycans in Cardiac Development”
H. Joseph Yost, PhD
Adjunct Professor, Department of Pediatrics
Professor, Department of Neurobiology & Anatomy
Director, Cardiac Development Research Center
University of Utah, Salt Lake City, UT
» more info from the Yost Lab web site

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 LHI Lecture
“Defining the Regulatory Pathways of Cardiac Progenitor Development”
Chulan Kwon, PhD
Staff Scientist
Gladstone Institute of Cardiovascular Disease
San Francisco, CA
» more info about Dr. Kwon's work from the Gladstone/Srivastava Lab web site

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Abstract:
Cardiac progenitor cells (CPCs) hold great potential for cardiac repair because of their unique nature to expand and differentiate into various cardiac cell types. However, the mechanisms underlying CPC self-renewal, proliferation and differentiation, a prerequisite for CPC based cardiac therapy, are still emerging. In this talk, I will discuss about the regulation of CPC development focused on the following topics:

• MicroRNA1 Regulation of Mesodermal Progenitors
• Role of Wnt/Beta-catenin and Notch signaling in CPC Development
• Post-translational Regulation of Beta-Catenin by Notch in Stem/Progenitor Cells

These studies reveal a regulatory network controlling CPC expansion and differentiation, and a novel role of Notch in negatively regulating Beta-catenin, which may be leveraged for regenerative approaches involving CPCs.

 LHI Lecture
“Activation of PDGF Signaling in Stromal Cell Development and Homeostasis”
Lorin Olson, PhD
Postdoctoral Fellow
Department of Developmental and Regenerative Biology
Mt. Sinai School of Medicine, New York

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Abstract:
Stromal cells arise from embryonic mesenchyme or neural crest to provide structure to an organ and modulate organ function. PDGF signaling coordinates mesenchymal progenitor cell development in many organs, but its role in maintaining stromal cells in the adult is unclear. Using conditional knockin approaches to activate PDGF signaling in the mouse, I found that increased PDGFR-alpha signaling in embryos or adult mice leads to connective tissue hyperplasia, or fibrosis, in many organs including the heart. Furthermore, vascular smooth muscle cells are known to have a plastic phenotype, and increased PDGFR-beta signaling in vivo alters the balance of VSMC activation/quiescence. PDGFR-beta appears to have a similar role in pericyte differentiation, which subsequently modulates capillary remodeling. These results identify PDGF receptors as important regulators of connective tissue and vascular homeostasis, with important implications for fibrotic diseases and potential regenerative approaches.

 LHI Lecture
“Nkx2-5 downstream targets and partners in cardiac development”
Cindy M. Martin, MD
Assistant Professor of Medicine
Director, Lillehei Heart Institute Stem Cll Flow Facility
Co-Director, Adult Congenital and Cardiovascular Genetics Clinic
University of Minnesota
» more info about Dr. Martin

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 LHI Lecture
“Stem cell-based cardiac disease modeling and regeneration”
Sean Wu, MD, PhD
Principal Faculty, Harvard Stem Cell Institute
Principal Investigator, Cardiovascular Research Center
Massachusetts General Hospital, Harvard Medical School
» more info about Dr. Wu from the Harvard Stem Cell Institute web site

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Abstract:
Stem cell-based therapy holds tremendous promise for a variety of cardiovascular diseases. The biology of cardiac differentiation from pluri- or multipotent stem cells provides critical insights into the logic of cardiac lineage commitment in precursor cells from different sources. We have previously described the isolation and characterization of developmental cardiac progenitor cells from embryonic stem cells and mouse embryos. We have recently identified a population of myocardial precursor cells in the postnatal heart that participates in neocardiomyogenesis after experimental injury. This seminar aims to delineate the origins and fates of cardiac progenitor cells during embryonic development and after myocardial injury. With the recent discovery of induced pluripotent stem (iPS) cells (i.e. somatic cells reprogrammed into pluripotent stem cells) the possibility exists that cardiovascular and metabolic disease may be modeled in vitro and drug screening may be applied to discover compounds that ameliorate the disease phenotype. An example of in vitro modeling of intracellular lipase deficiency disease and high-throughput drug screening using iPS cells will be presented.

 LHI Lecture
“Lineage Decision during ES differentiation”
Rita Perlingeiro, PhD
Associate Professor and Lillehei Endowed Scholar
Lillehei Heart Institute and Department of Medicine
University of Minnesota
» more info about Dr. Perlingeiro

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Abstract:
During this talk I will be discussing the role of some key molecular regulators involved in lineage determination as pluripotent cells commit to myogenic, hematopoietic and endothelial cell fates. I will cover our new insights on the role of the TGFβ signaling pathway, in particular the role of the accessory receptor, endoglin in these processes. The second part of my talk will focus on Pax3 and Pax7, and their ability to generate satellite cell engraftment and self-renewal from ES cells. Recent data involving the myogenic regenerative potential of iPS cells will also be discussed.