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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 less
The CRCIF was established to foster collaborative efforts aimed at elucidating the role of intermediate filaments (IFs) in the heart. Intermediate filaments constitute a class of cytoskeletal proteins in metazoan cells, however, different from actin microfilaments and tubulin microtubules, their function in cardiac cells is poorly understood. Unique from the other two components of the cytoskeleton, IFs are formed by cell type-specific proteins. Desmin is the main component of the IFs in the cardiac myocytes. We measured the consistent induction of desmin post-translational modifications (PTMs, such as phosphorylation, etc.) in various clinical and experimental models of heart failure. Therefore, one of our main focuses is to determine the contribution of desmin PTMs to the development of heart failure in different animal and clinical models.
Active Projects:
• Quantification of desmin PTM-forms in different forms of heart failure at the peptide level using mass spectrometry
• F...unctional assessment of the role of desmin PTMs in heart failure development using single site mutagenesis and biophysical methods
• Molecular characterization of desmin preamyloid oligomers using mass spectrometry, in vitro and in vivo imaging
• Assessment of the diagnostic and pharmacological value of desmin PTMs in heart failure development view less
The Foster Lab uses the tools of protein biochemistry and proteomics to tackle fundamental problems in the fields of cardiac preconditioning and heart failure. Protein networks are perturbed in heart disease in a manner that correlates only weakly with changes in mRNA transcripts. Moreover, proteomic techniques afford the systematic assessment of post-translational modifications that regulate the activity of proteins responsible for every aspect of heart function from electrical excitation to contraction and metabolism. Understanding the status of protein networks in the diseased state is, therefore, key to discovering new therapies.
D. Brian Foster, Ph.D., is an assistant professor of medicine in the division of cardiology, and serves as Director of the Laboratory of Cardiovascular Biochemistry at the Johns Hopkins University School of Medicine.
The main focus of Dr. Gilotra's research is understanding the pathophysiology and outcomes in inflammatory cardiomyopathies including myocarditis and sarcoidosis, as well as improvement of heart failure patient care through noninvasive hemodynamic monitoring and studying novel strategies to reduce heart failure hospitalizations. Additional investigations involve clinical research in advanced heart failure therapies including heart transplantation and mechanical circulatory support. Dr. Gilotra is the site Principal Investigator for the NIH/NHLBI funded Heart Failure Network trials.
Development and optimization of stem cell and regenerative therapies for heart failure and myocardial infarction.
CardiAMP Heart Failure Trial, Implantable Bioreactor for Prevention of Adverse Remodeling after Myocardial Infarction
Basic science investigations span an array of inquiries, such as understanding the basic mechanisms underlying cardiac dyssynchrony and resynchronization in the failing heart, and beneficial influences of nitric oxide/cGMP/protein kinase G and cGMP-targeted phosphdiesterase signaling cascades on cardiac maladaptive stress remodeling. Recently, the latter has particularly focused on the role of phosphodiesterase type 5 and its pharmacologic inhibitors (e.g. sildenafi, Viagra®), on myocyte signaling cascades modulated by protein kinase G, and on the nitric oxide synthase dysregulation coupled with oxidant stress.
The lab also conducts clinical research and is presently exploring new treatments for heart failure with a preserved ejection fraction, studying ventricular-arterial interaction and its role in adverse heart-vessel coupling in left heart failure and pulmonary hypertension, and testing new drug, device, and cell therapies for heart disease. A major theme has been with the use ...of advanced non-invasive and invasive catheterization-based methods to assess cardiac mechanics in patients.asive and invasive catheterization-based methods to assess cardiac mechanics in patients.
David Kass, MD, is currently the Director at the Johns Hopkins Center for Molecular Cardiobiology and a professor in cellular and molecular medicine. view more
Work in the Mahendra Damarla Lab focuses primarily on the field of vascular biology. Much of our research involves exploring alternatives to mechanical ventilation as a therapy for acute lung injury. We investigate mitogen-activated protein kinase-activated protein kinase 2 as a method to mediate apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3. We have also conducted research on the prevalence of confirmatory tests in patients hospitalized with congestive heart failure or chronic obstructive pulmonary disease (COPD).
The MR Research Laboratory focuses on developing and applying nuclear magnetic resonance (NMR) techniques and on measuring energy metabolites and metabolic fluxes with phosphorous (31P) and proton (1H) MRS in patients with ischemia, infarction and heart failure.
Specific studies include: Phosphorus MR studies of myocardial energy metabolism in human heart: We have used spatially localized phosphorus MR spectroscopy (MRS) to noninvasively measure high-energy phosphate metabolites such as ATP (adenosine triphosphate) and phosphocreatine (PCr) in the heart. The PCr/ATP ratio can change during stress-induced ischemia, and a protocol for stress-testing in the MR system has been developed which can detect the changes noninvasively in the anterior wall. Additionally, we've developed methods for noninvasively measuring the creatine kinase (CK) ATP energy supply and used it to measure the CK ATP energy supply in the healthy heart at rest and exercise, in human myocardial infarction, and in ...human heart failure.
Interventional MRI technology: We are developing an RF dosimeter that measures incident-specific absorption rates applied during MRI independent of the scanner and developing MRI-safe internal detectors for higher field use. Outcomes of this research include the "MRI endoscope" that provides real-time, high-resolution views of vessel anatomy and a radiometric approach to detect any local heating associated with the device.
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The Post Lab is involved in the Multi-Ethnic Study of Atherosclerosis (MESA), a collaborative study of the characteristics of subclinical cardiovascular disease (that is, disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease.
As MESA researchers, we study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Approximately 38 percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent.
Participants were recruited from six field centers across the United States, including Johns Hopkins University. Each participant received an extensive physical exam to determine a number of conditions, including coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, standard coron...ary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors.
Selected repetition of subclinical disease measures and risk factors at follow-up visits have allowed study of the progression of disease. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality.
Wendy S. Post, MD, MS, is an associate faculty, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, and a professor of medicine. view less
The Barouch Lab is focused on defining the peripheral cardiovascular effects of the adipocytokine leptin, which is a key to the understanding of obesity-related cardiovascular disease. Interestingly, many of the hormonal abnormalities seen in obesity are mimicked in heart failure. The research program will enhance the understanding of metabolic signaling in the heart, including the effects of leptin, exercise, sex hormones, and downstream signaling pathways on metabolism and cardiovascular function.
The lab also is working to determine the precise role of the “metabolic” beta-3 adrenergic receptor (ß3AR) in the heart and define the extent of its protective effect in obesity and in heart failure, including its role in maintaining nitric oxide synthase (NOS) coupling. Ultimately, this work will enable the exploration of a possible therapeutic role of ß3AR agonists and re-coupling of NOS in preventing adverse ventricular remodeling in obesity and in heart failure.
Lili Barouch, MD,... is an associate professor of medicine in the Division of Cardiology and a member of the Advanced Heart Failure and Cardiac Transplantation group at the Johns Hopkins University School of Medicine. view less
Work in the Wei Dong Gao Lab primarily focuses on heart failure and defining molecular and cellular mechanisms of contractile dysfunction. We use molecular biology and proteomic techniques to investigate the changes that myofilament proteins undergo during heart failure and under drug therapy. We're working to determine the molecular nature of nitroxyl (HNO) modification of tropomyosin.
The Weiss Lab, which features a multi-disciplinary team at Johns Hopkins as well as at Cedars Sinai Medical Center in Los Angeles, is dedicated to identifying the most important clinical, genetic, structural, contractile and metabolic causes of sudden cardiac death as well as the means to reverse the underlying pathology and lower risk.
Current projects include research into energy metabolism in human heart failure and creatine kinase metabolism in animal models of heart failure.
Robert G. Weiss, MD, is professor of medicine, Radiology and Radiological Science, at the Johns Hopkins University.
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