Summary:
Researchers in my laboratory use site-directed spectroscopy to define protein structural changes and motions that are crucial to muscle contraction and relaxation. Our approach combines mutagenesis, cell culture, peptide synthesis, muscle mechanics, magnetic resonance, and fluorescence. These spectroscopic measurements are performed during physiological function and detect dynamic disorder as well as ordered structural states in proteins. These studies have revealed that both contraction and relaxation, and their regulation, are driven by protein disorder-order transitions that are only loosely coupled to biochemical transitions. These fundamental discoveries in skeletal, cardiac and smooth muscle are now being applied to explore mechanisms and therapies for muscular dystrophy and heart failure.
The lecture will begin at noon in 3-100 Mayo Auditorium. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/MMA/index.html
A flyer for the lecture will be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
]]>The lecture will begin at noon in 3-100 Mayo Auditorium. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/MMA/index.html
A flyer for the lecture will be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
]]>Summary:
Dr. Iaizzo will present some of the novel images of functional cardiac anatomy his lab has obtained in recent years. In addition, he will present the feature of the free-access web site that his laboratory has developed: the Atlas of Human Cardiac Anatomy.
The lecture will begin at noon in 4-101 Nils Hasselmo Hall. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/NHH/index.html
A flyer for the lecture will be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
]]>Summary:
Cardiovascular cell therapy is more than 10 years old but cardiovascular disease still exceeds infection and cancer as a leading cause of death in most countries. Is cell therapy – either via exogenous delivery or innate mobilization of cells – an option for cardiac repair? In the next 25 years up to 15% of the population over the age of 65 in the US is projected to have heart failure. Therapeutic interventions that prevent/reverse atherosclerosis, prevent progression to HF after AMI, and halt the progressive functional deterioration in failing myocardium are all needed.
Prevention of CVD focuses on the prevention and reversal of atherosclerosis. Isolating new populations of stem cells from adult heart is a different aspect of the future. The final frontier is bio-engineering artificial organs to provide new tools for discovery and for therapy.
The lecture will begin at noon in 4-101 Nils Hasselmo Hall. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/NHH/index.html
A flyer for the lecture will be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
]]>Abstract:
Adult skeletal muscle has a remarkable regenerative capacity as it is capable of complete regeneration in response to an injury that destroys upwards of 90% of the tissue. This regenerative capacity is due to a muscle stem cell population (i.e. satellite cell population) that is resident in adult skeletal muscle. The myogenic stem cell (MSC) population is self-renewing, and a residual pool of stem cells, capable of supporting additional rounds of regeneration, is reestablished after each discrete episode of muscle injury. However, this capacity for self-renewal is finite. The exhaustion of the MSC pool is an important factor contributing to the clinical deterioration observed following myopathic diseases and aging (i.e. sarcopenia). Moreover, the fundamental regulatory mechanisms of myogenic stem cells (i.e. satellite cells) are incompletely understood. We have defined a novel marker, Foxk1, for the myogenic stem cell (MSC) population. Using a gene disruption strategy, we have observed that mice lacking Foxk1 have severely impaired muscle regeneration. We have further demonstrated that the Foxk1 null MSC population has perturbed cell cycle progression due to increased expression of the cyclin dependent kinase inhibitor, p21. These studies support the notion that Foxk1 is an essential regulator of the fate of the MSC population in adult skeletal muscle. Recent studies undertaken in our laboratory have identified additional nuclear factors that regulate Foxk1 activity and the myogenic stem cell population and serve as a platform to promote MSC activation and proliferation.
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The lecture will begin at noon in 4-101 Nils Hasselmo Hall. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/NHH/index.html
A flyer for the lecture will be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
Who: Daniel J. Garry, MD, PhD
Professor of Medicine
St. Jude Medical Endowed Chair in Cardiology
Director, Lillehei Heart Institute
Chief, Cardiovascular Division
What: LHI Lecture
"Fox, Sox and Muscle Stem Cells"
When: noon-1:00pm Wednesday, 10/1/2008
Where: 4-101 Nils Hasselmo Hall
312 Church St. SE, Minneapolis, MN
Abstract:
SMA is one of the most common autosomal-recessive disorders and is characterized by degeneration of spinal cord motor neurons. Most (94%) patients affected by SMA have deletion of SMN1 gene, but they retain a copy of the duplicate gene (SMN2) in their genome. The SMN2 gene produces defective SMN protein due to a C>T transition in exon7, which causes the skipping of exon7 during SMN mRNA maturation in 90% of transcripts. The SMN2 gene is therefore a therapeutic “target� for the treatment of SMA. The purpose of this study is to test the feasibility of the SFHR for genetically modifying the hSMN2 gene in cells obtained from human fetal chorionic villi of embryos, homozygous for the SMN1 deletion and mES cells derived from a mouse model for SMA (Smn-/-;hSMN2). Furthermore, the SFHR was optimized in order to clarify the molecular mechanism of action of the “transfected fragments� during the gene repair. To this purpose, was designed and constructed an “assay system.�
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The lecture will begin at 11:00am in 4-101 Nils Hasselmo Hall. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/NHH/index.html
A flyer for the lecture is also available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
Who: Antonio Filareto, PhD
Post-Doctoral Fellow in Human Genetics
Department of Biopathology & Diagnostic Imaging
Tor Vergata University Medical School, Rome
What: LHI Lecture
"Application and optimization of a gene targeting strategy called Small Fragment Homologous Replacement for the treatment of the Spinal Muscular Atrophy"
When: 11:00am Wednesday, 9/10/2008
Where: 4-101 Nils Hasselmo Hall
312 Church St. SE, Minneapolis, MN
The Lillehei Heart Institute will host a special lecture Thursday, April 17, 2008 by Annarosa Leri, MD. Dr. Leri is an Associate Professor in the Departments of Anesthesia and Medicine at Brigham and Women’s Hospital, Boston, MA. The title of her lecture is "Molecular control of cardiac progenitor cell differentiation."
Abstract
The Notch receptor mediates cell fate decision in multiple organs by modulating the expression of transcription factors that control differentiation. We have raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express the Notch1 receptor and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of the intracellular domain of Notch1 (N1ICD) in CPCs upregulates Nkx2.5 and promotes the formation of cycling myocytes in vitro. In contrast, transcription factors of vascular cell lineages are downregulated by Jagged1 stimulation of the Notch1 pathway. Importantly, inhibition of Notch1 signaling in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 activation favors the early commitment of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes corresponds to transit amplifying cells which condition the replicative capacity of the heart. The Notch1 pathway may have critical implications in the control of organ homeostasis and in the adaptation of the heart to pathologic states.
The lecture will begin at 1:00pm in the LHI Conference Room, 114 Dwan/KE. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/DVCCRC/index.html. Refreshments will be provided.
A flier for the lecture will also be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
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Abstract:
Cardiogenesis requires the generation of cardiac, smooth muscle, and endothelial cells. Using the single cell culture technique, we found that these three cell types can arise from a single cardiac progenitor. Interestingly, the multipotency of cardiac progenitors is progressively restricted during cardiogenesis, while the atrial progenitors, the late subset of Isl1 progenitors, maintain their bipotency until late. I will discuss the biological significance of the multipotency and plasticity of atrial lineage from both developmental and regenerative perspectives.
The lecture will begin at 2:00pm in the LHI Conference Room, 114 Dwan/KE. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/DVCCRC/index.html. Refreshments will be provided.
A flier for the lecture will also be available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
The lecture will begin at 9:00am in the LHI Education Center, Room 114 Dwan/KE. A map and directions to the building can be found at http://www.med.umn.edu/lhi/facilities/Maps_Directions.html.
A flier for the lecture is available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Refreshments will be provided.
The lecture will begin at 4:00pm in the Cardiology Conference Room, 299 VCRC. A map and directions to the location are available at http://www1.umn.edu/twincities/maps/VCRC/index.html. Hors d'oeuvres and beverages will be provided.
A flier for the lecture is available from the LHI web site at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested.
Abstract:
Recent projects to decipher genomic sequences of different species have opened up the genetic repertoire of living systems. However, it is necessary to evaluate the complete interactions across genes to relate the genotype to a specific phenotype. Genetic regulatory networks (GRN) refer to interactions between genes brought about through proteins that they code for. To date, the dominant approaches in GRN modeling are boolean and bayesian networks. The relationships in those networks are inferred from molecular biology studies, microarray data or transcription factor location data. However, these methods do not offer an explicit way to represent the underlying molecular regulatory mechanisms which are directly responsible for the behavior of GRN.
We present here a methodology which can account for the underlying regulatory molecular mechanisms - steady state modeling of GRN. We have also developed MATLAB based software - Steady State Gene Expression Simulator (SSGES) which accepts simple text based description of the GRN and generates the steady state mathematical model of the system. Using SSGES one can model regulatory mechanisms such as protein-DNA binding, protein-protein interactions, multiple operator sites, nucleocytoplasmic translocation of proteins and autoregulation of transcription factors. SSGES yields probability of gene expression, probability of protein expression and protein concentrations as an output. Further, SSGES can also be used to generate microarray type data.
In this talk, I will illustrate properties of S. cerevisiae GAL regulatory network and the cell cycle network through steady state modeling involving 11 transcription factors and 130 target genes. The input to the algorithm is the list of transcription factors that regulate the cell cycle and the microarray data wherein the particular response has been studied. We also discuss the salient features of underlying regulatory mechanisms such as sensitivity, robustness and functional advantage gained by the cell.
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The lecture will begin at 3:00pm in the LHI Education Center, Room 114 DVCCRC (aka KE). Refreshments will be provided. A flier for the lecture is available from the LHI website at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested. A map and directions to the location are also available from the web site at http://www.med.umn.edu/lhi/facilities/Maps_Directions.html.
Abstract:
The Role of Endoglin in Hemangioblast and Early Hematopoietic Development
The hematopoietic and endothelial lineages arise in mesoderm from a common bipotent progenitor – the hemangioblast. Although an in
vitro assay exists for the hemangioblast, very little is known about its regulation. In our search for hemangioblast regulatory molecules, we have discovered that endoglin, an ancillary receptor for several members of the TGF-β superfamily, plays a critical role in hemangioblast specification. My lab is using endoglin knockout and inducible ES cells to dissect the mechanism underlying endoglin’s function. We are also investigating the cascade of components associated with TGF-β signaling (Smads and ALKs) biochemically and genetically.
Skeletal Muscle Regeneration from Embryonic Stem Cells
Little progress has been made towards the generation of skeletal muscle progenitors from ES cells. This is due to the paucity of paraxial mesoderm formation during EB differentiation and to the lack of reliable identification and isolation criteria for skeletal muscle precursors. We are studying the potential of different myogenic regulatory factors to drive myogenesis from ES cells, and developing methods of purifying myogenic precursors. Inducible Pax3 expression enhances paraxial mesoderm, and allows skeletal myoblasts to be expanded from EB cultures. Upon dox withdrawal, these cells differentiate into muscle in
vitro. When transplanted into cardiotoxin-injured immunodeficient or dystrophin-deficient immunosuppressed mice, Pax3-induced cells demonstrate an exceptional potential for skeletal muscle regeneration, differentiating robustly into adult myofibers. Our focus now is to functionally evaluate the regenerative potential of ES/Pax3-derived myoblasts, and to understand the mechanism underlying their generation within paraxial mesoderm during ES/EB differentiation.
The lecture will begin at 3:00pm in the LHI Education Center, Room 114 DVCCRC (aka KE). Refreshments will be provided. A flier for the lecture is available from the LHI website at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested. A map and directions to the location are also available from the web site at http://www.med.umn.edu/lhi/facilities/Maps_Directions.html.
]]> The speaker for the LHI lecture Tuesday, 5/15/2007 will be Rita C. R. Perlingeiro, Ph.D. of UT Southwestern. The title of her lecture is "Regulation of embryonic stem cell differentiation."]]>Abstract:
Approximately 7.9 million Americans suffer from heart failure every year of which nearly 2.5 million develop Ischemic Mitral Regurgitation (IMR). Even with such high prevalence, little is known of the cause and progression of chronic IMR, resulting in the current lack of effective medical options for these patients. Current surgical repair techniques lack long-term durability leading to recurrence of IMR in ‹ 5 years and hence re-operation. Understanding the hemodynamic function and mechanics of the valve under normal, pathological and post-repair conditions would help us understand the pathological implications on valve function and also the reasons for failure of current repair techniques. Native porcine mitral valves were used in a novel in-vitro left-heart simulator that can generate in-vivo physiological and pathological hemodynamic conditions. The simulator is designed to impose precise geometric perturbations on the mitral valve both at the annular and sub-valvular levels and also allows the simulation of various surgical repair techniques on these geometrically perturbed valves. The hemodynamic function and mechanics of the valve under different conditions are quantified using different instrumentation and imaging procedures. The in-vitro left heart model can thus be used as a disease model for mitral valve disease and can also serve as a low-cost experimental test-bed for testing the feasibility and efficacy of novel mitral valve surgical repair techniques.
The lecture will begin at 3:00pm in the LHI Education Center, Room 114 DVCCRC (aka KE). Refreshments will be provided. A flier for the lecture is available from the LHI website at http://www.med.umn.edu/lhi/news_events/calendar.html; please feel free to print and distribute it to any who may be interested. A map and directions to the location are also available from the web site at http://www.med.umn.edu/lhi/facilities/Maps_Directions.html.
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