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The main focus of the Becker lab has been on the mechanisms and consequences of post-ischemic myocardial inflammation.
Genomic control of platelet function:
Aggregation of blood platelets initiates clotting in coronary arteries, the main cause of heart attacks. Our laboratory conducts experiments to understand how genes control platelet function. Through funding by the National Heart Lung and Blood Institute, we have performed candidate gene analysis, linkage studies, whole genome association studies, and now whole genome sequencing in about 2000 healthy subjects from families with early onset coronary artery disease. The subjects are siblings or offspring of an individual identified with coronary artery disease before age 60 in the GeneSTAR Research Program (Genetic Studies of Atherosclerosis Risk). We have identified a large number of common and rare genetic variants associated with platelet aggregation, and although some variants are located in genes known to be important in... the biology of platelet function, most are in non-protein coding regions of genes (introns) or in intergenic regions of the genome. To understand better how these variants influence platelet function, we created pluripotent stem cells from blood mononuclear cells in 257 genotyped GeneSTAR subjects and then transformed the stem cells to megakaryocytes, the source of platelets in the bone marrow. We have determined the entire transcriptome of these megakaryocytes to measure gene expression levels in an effort to functionally link genetic variation with platelet function. We are also interested in epigenetic effects which regulate the amount of gene transcription and resulting protein formation. We have done similar transcriptomic and proteomic studies in blood platelets as we have in stem cell-derived megakaryocytes.
Our goal is to identify new therapeutic targets for drug development to control excessive platelet aggregation and reduce the risk of heart attack in susceptible individuals. We also hope to use the genetic information to predict who is at greatest risk for platelet aggregation or bleeding, and tailor treatment to effectively apply individualized precision medicine.
The Becker laboratory also extends its cardiovascular work well beyond platelet function, as noted on the GeneSTAR Research Program website. view more
Edgar Miller Lab
Research in the Edgar Miller Lab focuses on nutrition, hypertension and kidney disease. Current projects include a National Heart, Lung, and Blood Institute study on dietary carbohydrate and glycemic index effects on markers of oxidative stress, inflammation and kidney function; and a National Institute of Diabetes and Digestive and Kidney Diseases randomized controlled trial that examines the effects of omega-3 fatty acid supplementation on urine protein excretion in diabetic kidney disease.
Gary Wand Lab
Research conducted in the Gary Wand Lab focuses on neuropsychoendocrinology; the neurobiology of substance abuse; physiogenetics and regulation of the stress response; and the relationship between stress and chemical dependency. Current studies seek to better understand the genetic determinants of the stress response and how excessive stress hormone production contributes to neurobiological disorders, including addiction.
Healthy Brain Program
The Brain Health Program is a multidisciplinary team of faculty from the departments of neurology, psychiatry, epidemiology, and radiology lead by Leah Rubin and Jennifer Coughlin. In the hope of revealing new directions for therapies, the group studies molecular biomarkers identified from tissue and brain imaging that are associated with memory problems related to HIV infection, aging, dementia, mental illness and traumatic brain injury. The team seeks to advance policies and practices to optimize brain health in vulnerable populations while destigmatizing these brain disorders.
Current and future projects include research on: the roles of the stress response, glucocorticoids, and inflammation in conditions that affect memory and the related factors that make people protected or or vulnerable to memory decline; new mobile apps that use iPads to improve our detection of memory deficits; clinical trials looking at short-term effects of low dose hydrocortisone and randomized to 28 day...s of treatment; imaging brain injury and repair in NFL players to guide players and the game; and the role of inflammation in memory deterioration in healthy aging, patients with HIV, and other neurodegenerative conditions. view more
Dr. Sohn's lab is interested in understanding how biological stress-sensors are assembled, detect danger signals and initiate stress response.
Innate immunity is the first line of defense against invading pathogens in higher eukaryotes. We are using in vitro quantitative biochemical assays and mutagenesis and x-ray crystallography to investigate the underlying operating principles of inflammasomes, a component of the innate immune system, to better understand biological stress sensors.
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
Kelly Metcalf Pate Lab
The Kelly Metcalf Pate Lab focuses on the role of platelets in the innate immune response to viral infection, and how modulating the response of platelets to infection alters the course of disease.
Platelets are known to participate in innate immunity through cytokine signaling and direct interactions with other cells, and the platelet has the potential to significantly influence disease outcomes. However, platelet immunology is still a relatively new discipline, and the downstream effects of platelet interactions with other immune cells have yet to be determined in the context of viral infection.
Current research in our lab aims to further characterize the platelet-monocyte interaction during acute viral infection with the goals of establishing methods of pharmacologically manipulating this association, and establishing how platelet binding to a monocyte influences the monocyte's susceptibility to lentiviral infection and the monocyte's interactions with endothelium.
Additio...nally, we are interested in the effect of physiologic stress on the platelet's future immune response to infection, and in the development and optimization of novel in vitro systems that better model in vivo conditions.
Molecular and Comparative Pathobiology
In the Lee Martin Laboratory, we are testing the hypothesis that selective vulnerability--the phenomenon in which only certain groups of neurons degenerate in adult onset neurological disorders like amyotrophic lateral sclerosis and Alzheimer's disease--is dictated by brain regional connectivity, mitochondrial function and oxidative stress. We believe it is mediated by excitotoxic cell death resulting from abnormalities in excitatory glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules.
We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmissi...on electron microscopy and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.
Dr. Fridman's research group invents and develops bioelectronics for Neuroengineering and Medical Instrumentation applications. We develop innovative medical technology and we also conduct the necessary biological studies to understand how the technology could be effective and safe for people.
Our lab is currently focused on developing the "Safe Direct Current Stimulation" technology, or SDCS. Unlike the currently available commercial neural prosthetic devices, such as cochlear implants, pacemakers, or Parkinson's deep brain stimulators that can only excite neurons, SDCS can excite, inhibit, and even sensitize them to input. This new technology opens a door to a wide range of applications that we are currently exploring along with device development: e.g. peripheral nerve stimulation for suppressing neuropathic pain, vestibular nerve stimulation to correct balance disorders, vagal nerve stimulation to suppress an asthma attack, and a host of other neuroprosthetic applications.
M...edical Instrumentation MouthLab is a "tricorder" device that we invented here in the Machine Biointerface Lab. The device currently obtains all vital signs within 60s: Pulse rate, breathing rate, temperature, blood pressure, blood oxygen saturation, electrocardiogram, and FEV1 (lung function) measurement. Because the device is in the mouth, it has access to saliva and to breath and we are focused now on expanding its capability to obtaining measures of dehydration and biomarkers that could be indicative of a wide range of internal disorders ranging from stress to kidney failure and even lung cancer.
The Robinson Lab studies the way in which mechanical stress guide and direct the behavior of cells, including when they are part of tissues, organs and organ systems.
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.
The O’Rourke Lab uses an integrated approach to study the biophysics and physiology of cardiac cells in normal and diseased states.
Research in our lab has incorporated mitochondrial energetics, Ca2+ dynamics, and electrophysiology to provide tools for studying how defective function of one component of the cell can lead to catastrophic effects on whole cell and whole organ function. By understanding the links between Ca2+, electrical excitability and energy production, we hope to understand the cellular basis of cardiac arrhythmias, ischemia-reperfusion injury, and sudden death.
We use state-of-the-art techniques, including single-channel and whole-cell patch clamp, microfluorimetry, conventional and two-photon fluorescence imaging, and molecular biology to study the structure and function of single proteins to the intact muscle. Experimental results are compared with simulations of computational models in order to understand the findings in the context of the system as a whole....
Ongoing studies in our lab are focused on identifying the specific molecular targets modified by oxidative or ischemic stress and how they affect mitochondrial and whole heart function.
The motivation for all of the work is to understand
• how the molecular details of the heart cell work together to maintain function and
• how the synchronization of the parts can go wrong
Rational strategies can then be devised to correct dysfunction during the progression of disease through a comprehensive understanding of basic mechanisms.
Brian O’Rourke, PhD, is a professor in the Division of Cardiology and Vice Chair of Basic and Translational Research, Department of Medicine, at the Johns Hopkins University. view less
Sherita Golden Lab
Research in the Sherita Golden Lab focuses on identifying endocrine risk factors associated with the development of diabetes and cardiovascular disease. We conduct our research by incorporating measures of hormonal function into the design of clinical trials of cardiovascular risk modification, observational studies of incident cardiovascular disease and diabetes, and studies evaluating diabetic complications.
Todd Dorman Lab
Research conducted in the Todd Dorman Lab examines the use of informatics in intensive care settings as it relates to remote patient monitoring, safety and management strategies. Specific areas of interest include the surgical stress response; aminoglycoside antibiotics; fungal infections; renal failure; pharmacokinetic models of drug administration; and ICU triage and its impact on disaster preparedness.
Elevation of O-GlcNAc levels modulates numerous pathways in a manner consistent with increased cell survival, including the expression of heat shock proteins. The Zachara Lab's goal is to understand the O-GlcNAc regulated stress response, how this can be manipulated to improve patient outcome and how this response is misregulated in disease.