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Research in the Anderson laboratory focuses on cellular signaling and ionic mechanisms that cause heart failure, arrhythmias and sudden cardiac death, major public health problems worldwide. Primary focus is on the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII). The laboratory identified CaMKII as an important pro-arrhythmic and pro-cardiomyopathic signal, and its studies have provided proof of concept evidence motivating active efforts in biotech and the pharmaceutical industry to develop therapeutic CaMKII inhibitory drugs to treat heart failure and arrhythmias.
Under physiological conditions, CaMKII is important for excitation-contraction coupling and fight or flight increases in heart rate. However, myocardial CaMKII is excessively activated during disease conditions where it contributes to loss of intracellular Ca2+ homeostasis, membrane hyperexcitability, premature cell death, and hypertrophic and inflammatory transcription. These downstream targets a...ppear to contribute coordinately and decisively to heart failure and arrhythmias. Recently, researchers developed evidence that CaMKII also participates in asthma.
Efforts at the laboratory, funded by grants from the National Institutes of Health, are highly collaborative and involve undergraduate assistants, graduate students, postdoctoral fellows and faculty. Key areas of focus are:
• Ion channel biology and arrhythmias
• Cardiac pacemaker physiology and disease
• Molecular physiology of CaMKII
• Myocardial and mitochondrial metabolism
• CaMKII and reactive oxygen species in asthma
Mark Anderson, MD, is the William Osler Professor of Medicine, the director of the Department of Medicine in the Johns Hopkins University School of Medicine and physician-in-chief of The Johns Hopkins Hospital. view more
Daniel Raben Laboratory
The Raben Laboratory is focused on understanding the biochemistry and chemistry underlying the molecular aspects involved in regulating lipid metabolizing signaling enzymes and the physiological roles of this regulation. Controlling lipid-metabolizing enzymes involves modulating their sub-cellular distribution and their intrinsic enzymatic activity. Researchers in the Raben laboratory examine three families of lipid-metabolizing signaling enzymes: diacylglycerol kinases, phospholipases D, and phospholipases C.
The Jun O. Liu Laboratory tests small molecules to see if they react in our bodies to find potential drugs to treat disease. We employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases. Among the biological processes of interest are cancer cell growth and apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation.
The Bumpus Laboratory uses mass spectrometry and molecular pharmacology-based approaches to study the biotransformation of clinically used drugs by the cytochromes P450s. Specifically, we are studying ways to define a role for cytochrome P450-dependent metabolites in the drug-induced acute liver failure that is associated with certain antiviral drugs used to treat HIV and hepatitis C. Our long-term goal is to gain information that can be used to develop therapies that are devoid of toxic events by preventing the formation of a toxic metabolite or by developing strategies for preventing toxicity using concomitant therapy.
The Gabelli lab research is focused on structural, mechanistic and functional aspects of enzyme activation that play a role in the biology of human diseases such as cancer, parasitic infection and cardiovascular disease. Their work seeks to:
1. Understand how molecular events at the recognition level coordinate and trigger events in the cells
2. Translate structural and mechanistic information on protein:protein interactions at the cytoplasmic level into preventive and therapeutic treatment for human disease.
To achieve a comprehensive understanding, they are studying cytoplasmic protein-protein interactions involved in regulation of pathways such as PI3K and Sodium Voltage gated channels. Their research integrates structural biology and chemical biology and it is focused on drug discovery for targeted therapies.
Seth Margolis Laboratory
The Seth Margolis Laboratory studies the signaling pathways that regulate synapse formation during normal brain development to try to understand how, when these pathways go awry, human cognitive disorders develop.
We use Ephexin5 to study the molecular pathways that regulate restriction of excitatory synapse formation and their relevance to the pathophysiology of Angelman syndrome.
The Shanthini Sockanathan Laboratory uses the developing spinal cord as our major paradigm to define the mechanisms that maintain an undifferentiated progenitor state and the molecular pathways that trigger their differentiation into neurons and glia. The major focus of the lab is the study of a new family of six-transmembrane proteins (6-TM GDEs) that play key roles in regulating neuronal and glial differentiation in the spinal cord. We recently discovered that the 6-TM GDEs release GPI-anchored proteins from the cell surface through cleavage of the GPI-anchor. This discovery identifies 6-TM GDEs as the first vertebrate membrane bound GPI-cleaving enzymes that work at the cell surface to regulate GPI-anchored protein function. Current work in the lab involves defining how the 6-TM GDEs regulate cellular signaling events that control neuronal and glial differentiation and function, with a major focus on how GDE dysfunction relates to the onset and progression of disease. To solve the...se questions, we use an integrated approach that includes in vivo models, imaging, molecular biology, biochemistry, developmental biology, genetics and behavior. view more
Stephen Desiderio Laboratory
The Stephen Desiderio Laboratory is interested in molecular and genetic mechanisms responsible for development of the immune system, with a particular focus on V(D)J recombination and its role in immunity. This process, which builds antigen-receptor genes from discrete gene segments, shares mechanistic features with transposition and, as a potential source of DNA damage, is subject to tight control.
We also focus on the generation of immune cells from blood-forming stem cells in the bone marrow. Our focus is on how hedgehog--a critical morphogenic signal--signaling in stromal cells promotes immune development, we hope to be better able to manipulate human immune responses for future therapeutic uses.
We are also interested in how immune cells respond to environmental cues. We have uncovered a novel way in which calcium is regulated in response to antigen receptor stimulation and are testing whether this mechanism contributes to the decision between activation and anergy, which is... when certain signals block immune cells' responsiveness. view more
The Tomaselli lab is focused on the fundamental basis of excitability in the heart.
We study this problem at multiple levels of integration from molecules and cells to abnormalities of heart rhythm in patients.
At a molecular level, they seek to understand how ion channel proteins perform their essential tasks, in particular they are interested in a key paradox how these channels permit the flow of millions of ions a second, yet do this with exquisite selectivity (sodium channels allow sodium ions but not similarly sized and charged potassium ions).
More recently they have turned their attention to the regulation of sodium and potassium channels by important cellular signaling systems which are involved in not only in how the heart conducts electricity but also the force with which it contracts.
The diseased heart undergoes a series of changes, initially compensatory but ultimately maladaptive, that increase the risk of potentially lethal arrhythmias. These changes are comm...only referred to as remodeling. Dr. Tomaselli’s group is studying the remodeling process in animal models of heart failure using gene expression, protein and ionic current measurements. They have developed a canine microarray for the broad-based study of gene expression in the failing canine heart.
At the ultimate level of integration they are examining the role of implanted defibrillators (ICDs) in patients with diseased, remodeled hearts. They have initiated a study referred to as PROSe-ICD (PRospective Observational Study of the ICD in the prevention of sudden death).
PROSe-ICD has enrolled nearly 800 patients all have undergone detailed clinical and electrocardiographic studies as well as having blood collected for performing genetic and proteomic analyses. Over 25% of this cohort has undergone detailed cardiac imaging (MR and CT) and spectroscopy to identify imaging based markers of risk of sudden death. The overarching goal is to better understand the mechanisms of sudden arrhythmic death and to develop better predictors of risk of this devastating outcome.
Gordon F. Tomaselli, MD, is the chief of the Johns Hopkins Division of Cardiology and co-director of the Heart and Vascular Institute. view more