Our scientists use physical science methods to study biological systems. Specifically, our research is focused in the areas of EPR, MR physics and brain imaging, and redox research.
MR Physics & Brain Imaging Research
National Biomedical EPR Center
Redox & Bioenergetics Shared Resource
Redox Biology Program
MPI: Dara Frank / Jimmy Feix
Type III Effector-Cofactor Dynamics within the Cellular Environment
The major goals of this project are to use genetic, biochemical and biophysical techniques to understand how ExoU, a type III secreted phospholipase, manipulates the host ubiquitin system, and to uncover new insights into mammalian cellular biology and provide unique targets and biological tools for translational applications.
Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol
We will evaluate the chemopreventive potential of Mito-HNK, a mitochondria-targeted compound, using both in vitro and in vivo models of lung adenocarcinoma (LUAD) and determine its mechanism of action, to determine its efficacy for inhibiting LUAD progression and metastasis and its suitability for human clinical trials.
MPI: Ming You / Laura Kresty / Balaraman Kalyanaraman
Chemoprevention of Lung Cancer by Targeting Lonidamine to Mitochondria
New and effective preventive agents for lung cancer are urgently needed. Selectively inhibiting cancer cell mitochondrial bioenergetics is a novel preventive strategy for lung cancer that has a great potential. By modifying lonidamine (LON), we created the mitochondria-targeted agent, Mito-LON, as a new, safe and potent preventive agent that robustly inhibits bioenergetics and induces autophagic cell death of cancer cells. We will systematically and thoroughly evaluate the chemopreventive potential of Mito-LON using both in vitro and in vivo models of lung cancer and determine its primary mechanism(s) of action.
New treatment monitoring biomarkers for brain tumors using multiparametric MRI with machine learning
The goal of this project is to develop novel multiparametric MRI biomarkers that precisely identify regions of brain tumor within areas of contrast-enhancement and peritumoral edema, which cannot be identified using standard MRI.
Establishing the Clinical Utility of a Consensus DSC-MRI Protocol
This study represents the next step to develop a consensus regarding the post-processing of DSC-MRI data. The goal is to establish with data a national consensus and then with this consensus set references regarding evaluating brain tumors and their treatments.
PI: Candice S. Klug
Lpt protein-mediated transport of LPS
The major goal of this project is to gain insights into the mechanism of LPS transport across the periplasm of Gram-negative bacteria to enable rational antibiotic drug design. This will be accomplished through the study of LptA, LptC, and LPS using site-directed spin labeling EPR spectroscopy and other biophysical techniques.
PI: Michael Lerch
Regulation of β2-adrenergic receptor signaling by post-translational modifications
G-protein-coupled receptors are a large and diverse class of cell surface receptors responsible for regulating nearly every physiological process in the human body and are therefore important targets for drug development. In this project, we aim to elucidate the molecular basis for modulation of β2-adrenergic receptor signaling by two post-translational modifications (PTMs), glycosylation and palmitoylation, using a complementary combination of continuous-wave and pulsed electron paramagnetic resonance techniques and functional assays. By detailing the effects of these PTMs on the conformational landscape, the results from these studies will provide insight into the understudied yet critical role of these PTMs as regulators of receptor signaling, thereby increasing researchers' ability to rationally design drugs to achieve the desired therapeutic effect.
MPI: Candice Klug / Michael Lerch
Development of High-Throughput, High-Sensitivity EPR Sample Handling Capabilities
for Biomedical Research
Electron paramagnetic resonance (EPR) spectroscopy is a critically important technique in biomedical research with a unique ability to detect naturally occurring or engineered unpaired electrons in complex biological environments. We will develop two innovative EPR spectrometer technologies with outstanding sample sensitivity that are easy to use and widely available to the scientific community. The resulting state-of-the-art prototypes will provide a transformative increase in throughput that will enable a wide range of new applications in biomedical EPR spectroscopy studies including structural biology, metalloprotein research, redox biology, rational drug design, and clinical diagnostics for a range of disease areas.
Probing the Role of Tetrahydrobiopterin in Cerebral Palsy by Using Transgenic Rabbits
There is a paucity of effective treatments for cerebral palsy and this proposal tests whether an essential enzyme co-factor is involved in brain injury before birth. Using animals in which genes have been altered in their genome by genetic engineering methods, and advanced methods of magnetic resonance imaging, the cellular and genetic basis of brain regional injury will be investigated. These studies will lead to a better understanding how treatment with the same co-factor can reverse the movement disorders caused by insults to the fetal brain before birth.
Quantitative (Perfusion and Diffusion) MRI Biomarkers to Measure Giloma Response
This U01 application proposes the development and validation of a combined perfusion and diffusion MRI (magnetic resonance imaging) methods for use in clinical trials to evaluate the response of brain tumors to targeted therapies. Given that standard MRI methods to monitor treatment response have been found lacking this addresses an urgent clinical need. The perfusion technology is based on developments made over the past 12 years in the PI's laboratory and therefore may represent the most comprehensive and accurate solution to monitoring tumor vessel growth. This combined with recent advances in diffusion imaging, which provide complementary information about tumor cell invasion, has the potential to change the way by which brain tumor treatments are monitored and aid in the discovery of new treatments and combinations. Finally, working in close collaboration with an industrial partner, the proven technical methods resulting from this study will be translated into a low cost commercial software platform for widespread use within the QIN and beyond.
PI: Jacek Zielonka
AHW/Limited Needs Funding
Small Volume Multi-well Plate Dispensers for Screening Drug Combinations
The long-term goals of the research projects supported by the requested instrumentations are to identify novel combinations of mitochondria-targeted experimental bioactive agents with clinically relevant drugs for the treatment of pancreatic and other cancers; identify bioavailable, NADPH oxidase-2-specific inhibitors that will yield potential novel agents to prevent post-traumatic epilepsy and other pathologies associated with increased NADPH oxidase-2 activity, including neurodegenerative and cardiovascular diseases and select types of cancer; and establish a drug combination screening workflow based on custom-synthesized bioactive agents and commercially available chemical libraries.
MCW CRI 18-318
Molecular Determinants of Drug Sensitivity and Resistance to Gallium-based Therapy in Pediatric Brain Tumors
PI: Kathleen Schmainda
MCW CRI 19-305
Obtaining Preclinical Evidence for a Novel Iron-Targeted Therapy for Recurrent Pediatric Glioblastoma