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 Key Personnel
Research Interests
http://macbeth.clark.jhu.edu/baderlab/index.php/Main_Page
My lab is interested in understanding how neuronal and nonneuronal cells in the body detect changes in ambient temperature. Increases or decreases in tissue temperature can cause pain, pleasure, or homeostatic changes in mammals, depending upon their direction, magnitude, and anatomical location. The molecular basis of this thermosensation, however, is very poorly understood. We previously identified two heat-gated ion channels that are expressed in distinct subsets of peripheral neurons within the pain pathway. One of these proteins, TRPV1 (VR1), is a channel that can be activated not only by noxious heat (>43 C), but also by protons and by capsaicin (the main pungent ingredient in 'hot' peppers). The second channel, TRPV2, is activated by temperatures exceeding 52 C, but is insensitive to protons or capsaicin. Since then, we and others have identified several additional members of the TRP ion channel family that can be activated by either increases (TRPV3, TRPV4) or decreases (TRPM8) in temperature. Through a multidisciplinary approach involving molecular biology, biochemistry, calcium imaging, electrophysiology and mouse behavior, we are focusing on the following goals: 1)Using mouse knockouts of temperature-gated ion channels to clarify their roles in pain and temperature sensation. 2) Dissecting the mechanisms by which these molecules are activated by increases or decreases in ambient temperature. 3) Understanding how nonneuronal cells that express temperature-gated channels contribute to the process of thermosensation. http://biolchem.bs.jhmi.edu/members/facultydetail.asp?PersonID=666
We use chemical approaches to study cell signal transduction hormonal control of circadian rhythm and gene regulation. We are interested in understanding the basis for molecular recognition of protein kinases. We employ substrate analogs, site-directed mutagenesis, and kinetic methods to elucidate protein kinase-substrate relationships. We are also pursuing the mechanism and inhibition of melatonin production. A new protein engineering method called expressed protein ligation, which allows for the ligation of synthetic peptides to recombinant proteins developed by us in collaboration with Tom Muir's laboratory, is being applied to these systems and others to elucidate protein function. We have also developed selective HAT (histone acetyltransferase) and demethylase inhibitors to investigate the role of the protein acetylation and methylation. http://www.hopkinsmedicine.org/pharmacology/research/cole.html
Our lab is focused on developing novel perturbation techniques and thereby understanding the molecular mechanisms underlying rapid biological processes such as cell migration. With the previously developed technique, we can inducibly manipulate the activity of various signaling molecules involved in cell migration, such as small GTPases and membrane lipids in intact living cells with a second timescale. This method is extremely powerful, as it has been successfully applied to several different biological systems and has resolved two long-standing mysteries in signal transduction: the regulatory mechanisms governing potassium ion channels (concluded with a Bertil Hille's group at University of Washington), and the membrane targeting mechanisms of small GTPases. We will craft a program of study that will quantitatively and spatiotemporally define migration in chemotactic cells. We hypothesize that there is only a handful of critical molecular steps regulating a symmetry breaking event that initiates migration. If true, this model would usher in a new paradigm for cellular migration. With the strong interdisciplinary background, we will personify the kind of work for which our lab stands: innovative research that drives science forward. http://www.hopkinsmedicine.org/cellbio/profiles/profdisplay.cfm?senduserID=336&sendpage=directory
Our lab has been interested in studying cell surface molecules that mediate signal transduction in the nervous system. One area of our research focuses on the molecular and cellular mechanisms by which potassium channels are assembled and regulated. The native potassium channel complex contains pore-forming subunits, modulatory auxiliary subunits and posttranslational enzymes (e.g.., kinases and phosphotases). The combinatorial and regulatory assembly of these diverse proteins has been implicated in neuronal plasticity. We also identified and characterize novel compounds that either inhibit or activate potassium channels. Investigation of these chemicals may provide leads for therapeutics. Our long term goal is to understand the macromolecular organization and regulatory network of native ion channel complexes. http://www.molecularinteraction.org
We are interested in the biochemical and molecular mechanisms used by membrane transport systems (pumps and carriers). Most of our work has used bacterial examples, both for their simplicity and because these model systems are suited to a combination of molecular genetics and biochemistry. By analyzing wild type and genetically engineered variants, we hope to correlate kinetic and structural properties to answer the following kinds of questions: What architectural features are essential to membrane transport proteins? Can we use the amino acid sequence to predict substrate specificity, selectivity or transport directionality? And what can we learn about biochemical mechanism and cellular regulation from those aspects of protein structure that are conserved during evolution? Recently, these questions have become especially relevant to understanding the origins of cystic fibrosis, a disease of transcellular fluid movement. The defect in cystic fibrosis is now attributed to an abnormal protein, CFTR, whose sequence suggests it is involved in ATP-dependent transport. Our most recent efforts deal with the biochemistry and molecular biology of this important protein. https://jshare.johnshopkins.edu/lye2/public_html/
Dr. Tomaselli is a Professor of Medicine in the Division of Cardiology & Molecular Medicine at the Johns Hopkins University School of Medicine. He is Chief of the Division of Cardiology. In this role he attends the clinical electrophysiology laboratory, teaches physiology, pathophysiology, and molecular medicine to first and second year medical students, and has an active basic laboratory research program. Dr. Tomaselli is known for his work on cardiac electrophysiology and arrhythmias, and his laboratory interests include the structure and function of ion channel genes and proteins, and molecular genetic changes in excitability molecules which occur in the human heart failure. He is board certified in cardiovascular diseases, and clinical electrophysiology and pacing. He is a Past President of the Cardiac Electrophysiology Society, the Chairman of the Committee on Scientific Sessions Programming (CSSP) of the American Heart Association and a member of the leadership Committee for the Council on Basic Cardiovascular Sciences of the American Heart Association. He is a Board Member of the Heart Rhythm Society (HRS) and prior Basic Science Chair of the Program committee for HRS Scientific Sessions. He serves on the editorial board of Circulation, Journal of Cardiac Electrophysiology and is Deputy Editor of Circulation Research and is a former permanent member and now on reviewer reserve of the Electrical Signaling, Ion Transport and Arrhythmias [ESTA] Institutional Review Group at the National Institutes of Health, The National Heart Lung & Blood Institute. http://www.reynolds.jhmi.edu/personnel/pi_profile/tomaselli.html
Intracellular Ca2+ signals comprise a lingua franca of life at the microscopic scale. For example, Ca2+ inflow through Ca2+ channels (a voltage-controlled, Ca2+-entry porthole into cells) starts a chain of events leading to initiation of the heartbeat, or even to the neuro-synaptic transmission (6) underlying our very thoughts. Moreover, longer-term changes in [Ca2+] control gene expression in neurons. It is no wonder that Ca2+ signals are as critical and ubiquitous to biological systems, as are voltage signals to electronic circuits. Much of our work thus focuses on the "transistors" of Ca2+ signalingævoltage-gated Ca2+ channels. Unmasking their secrets critically deepen understanding of normal biology, and promise to reveal new therapies for disease. What tools do we use? Ca2+ signals research provides a remarkable opportunity for the fruitful combination of mathematics, engineering, and molecular experimentation. Channel functions can be quantitatively probed with patch-clamp electrophysiology (1-6) and a biological fluorescence technique called FRET (4). The latter approach offers a dynamic readout of molecular motions in single living cells. Molecular biology (1-5), biochemistry (1,3,4), and virology (5) permit exquisite molecular manipulation of channels. Experiments and theory are wedded with mathematical modeling (2,5). What’s an example of our discovery? Calmodulin (CaM) --a central Ca2+-sensing molecule in biology-- is comprised of two ball-like ends attached by a flexible linker. We have discovered a key rationale for this mysterious bio-architectural design: each ball selectively demodulates different streams of information from a common Ca2+ signal, and then each ball appropriately affects channel function in a distinct way (1-4). Such features make CaM the biological equivalent of a stereo receiver, capable of extracting two channels of information from a common radio signal. Using viral gene transfer in adult heart cells, we found that CaM-mediated feedback on cardiac L-type Ca2+ channels is the dominant control factor in controlling the cardiac action potential duration, a vital excitability parameter whose prolongation in heart failure and long QT syndromes precipitates life-threatening arrhythmias. The latter results furnish insight into therapeutic approaches for cardiac arrhythmias in abnormal QT conditions, such as drugs modulating CaM/L-type channel interactions and gene therapy with engineered CaMs. |
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