Work in the Marek Mirski lab explores the subcortical mechanisms of seizure propagation and cortical synchrony. The primary goal of our research is to develop methodologies for inhibiting seizures using site-specific subcortical electrical stimulation. Our identification of synaptically linked subcortical elements that contribute to seizure propagation has led to FDA-sanctioned phase III clinical trials to assess the use of targeted thalamic stimulation in patients with intractable seizures. We also conduct clinical research on the treatment of acute head injury, elevated intracranial pressure, cerebral edema, ischemic stroke and ICU sedation.

Our broad research goals are to identify and validate novel molecular therapeutic targets in hematopoietic malignancies. We are interested in the identification and pre-clinical development of novel targeted therapies, and, in particular, the “translational” step of this research by using correlative studies to incorporate these novel therapies into existing treatments. Our research is of particular interest to those who wish to be involved in directly translating the results of laboratory bench work into meaningful benefits for patients. Currently, we are actively involved in the pre-clinical and clinical development of small molecule kinase inhibitors targeting the FLT3 signaling pathway in acute myeloid leukemia. We are interested in 3 compounds in particular- AC220, a FLT3/KIT inhibitor; crenolanib,a selective FLT3 inhibitor with activity against resistant point mutations; and PLX3397, another inhibitor of KIT and FLT3. The active projects in the lab include: 1) Characterization of cytotoxic responses of different hematologic malignancies to FLT3 and KIT kinase inhibition; 2) Examination of the interaction of bone marrow stroma and stroma-derived cytokines on the efficacy of these inhibitors; 3) Examination of the differential effect of FLT3 inhibition versus combined FLT3/KIT inhibition on acute myeloid leukemia and bone marrow progenitor cells; and 4) Correlative laboratory studies using blood and marrow samples from patients treated with FLT3 inhibitors, with the aim of developing predictive models for clinical response.

The Hey-Kyoung Lee Lab is interested in exploring the cellular and molecular changes that happen at synapses to allow memory storage. We use various techniques, including electrophysiological recording, biochemical and molecular analysis, and imaging, to understand the cellular and molecular changes that happen during synaptic plasticity. Currently, we are examining the molecular and cellular mechanisms of global homeostatic synaptic plasticity using sensory cortices as model systems. In particular, we found that loss of vision elicits global changes in excitatory synaptic transmission in the primary visual cortex. Vision loss also triggers specific synaptic changes in other primary sensory cortices, which we postulate underlies sensory compensation in the blind. One of our main research goals is to understand the mechanisms underlying such cross-modal synaptic plasticity. We are also interested in elucidating the events that occur in diseased brains. In collaboration with other researchers, we are analyzing various mouse models of Alzheimer's disease, especially focusing on the possible alterations in synaptic plasticity mechanisms.

The Johns Hopkins Head and Neck Cancer Tissue Bank enrolls patients and collects research specimens from Head and Neck Tumor patients, both cancerous and benign, with particular focus on Head and Neck Squamous Cell Cancer patients. It provides specimens to researchers both within the institution and outside.

Our work is focused on the translational human in vivo and ex vivo assessments of right ventricular (RV) function in the setting of pulmonary hypertension. Among patients with group I pulmonary arterial hypertension PAH, those with systemic-sclerosis-associated PAH (SSc-PAH) have a particularly poor prognosis and less optimal response to PAH-guided therapy. Using in vivo pressure-volume catheterization of the right ventricle, we have uncovered key deficiencies in resting and reserve RV function in the SSc-PAH group when compared to idiopathic PAH (IPAH) patients. These studies have uncovered key discoveries with regards to right ventricular-pulmonary arterial (RV-PA) coupling in PAH. In the lab, by studying myofilament function from RV endomyocardial biopsies from these same patients, we have uncovered corresponding deficiencies in myofilament contractility and calcium sensitivity as well. Ongoing work is directed towards determining the underlying mechanism of these findings, which will hopefully lead to therapeutic applications for RV failure in SSc-PAH. Further endeavors are directed towards studying RV failure in other populations, including exercise-induced PH, PH secondary to left-heart disease, and the left ventricular assist device population.

Work in the Hsin-Chieh Yeh Lab focuses on clinical trials and cohort studies of diabetes, obesity and behavioral intervention, cancer and hypertension. Recent investigations have focused on novel risk factors and complications related to obesity and type 2 diabetes, particularly lung function, smoking and cancer. We recently co-led a randomized clinical trial of tailored dietary advice for consumption of dietary supplements to lower blood pressure and improve cardiovascular disease risk factors in hypertensive urban African Americans.

Researchers in the Henry Michtalik Lab are interested in patient safety—particularly as it relates to patient census statistics and acute to primary care transitions—and quality improvement and systems management.

Research in the Thomas Grader-Beck Lab aims to understand the pathogenesis of systemic autoimmune diseases—particularly systemic lupus erythematosus (SLE) and Sjögren’s syndrome—by taking a translational approach. Autoantibodies (antibodies that target self-molecules) are believed to contribute significantly to the disease process. We are studying mechanisms that may make self-structures immunogenic. We theorize that certain post-translational antigen modifications, which can occur in infections or malignant transformation, result in the expression of neoepitopes that spread autoimmunity in the proper setting. The team has combined studies that employ a number of mouse strains, certain gene-deficient mice and human biological specimens.

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.

The Todd Brown Lab focuses on metabolic, endocrine and skeletal abnormalities in HIV-infected patients, particularly as these factors relate to aging. Our studies take an epidemiologic approach to understanding the occurrence and prevalence of insulin resistance, diabetes, and anthropometric changes in HIV patients and their relationship to antiretroviral treatment.