In the Department of Biophysics, 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.
The Department of Biophysics is home to the National Biomedical EPR Center, which is the most extensive electron paramagnetic resonance (EPR) facility in the nation. Research conducted within the EPR Center includes technological innovation and application of new techniques to biological problems. The main focus areas are spin labeling of proteins and lipids, structural and conformational changes of proteins, redox changes at the active site of metallo-proteins, and oxidants and free radical formation in tumorigenesis and tumor progression and in drug resistance in cancer. The EPR Center houses an array of internally developed and commercial EPR instrumentation, a specialized engineering/development staff capable of steadily and significantly advancing the state-of-the-art technology for biomedical applications of EPR spectroscopy, and a scientific staff with broad expertise.
MR Physics & Brain Imaging Research
Scientists in the Department of Biophysics have been engaged in magnetic resonance (MR) research for more than 25 years, beginning with the installation of one of the first 1.5 Tesla scanners produced by GE Healthcare. Early papers were concerned mostly with the development of surface coils tailored to nearly every body part in the context of musculoskeletal radiology. MCW students and faculty published the first paper on functional MRI (fMRI) in 1992 and on resting-state fMRI in 1995. Technology development continued to be important, including the introduction of the local gradient coil for fMRI and development of the widely used fMRI software program AFNI (Analysis of Functional NeuroImages). Currently, emphasis on fMRI technology continues, but, increasingly, MRI research in the Department of Biophysics involves mechanisms of fMRI contrast in the brain and applications of fMRI to neurological and psychiatric disorders (e.g., early disease detection, precision disease prevention, prediction of disease development, and assessment of treatment efficacy in Alzheimer’s disease research). Strong interdisciplinary collaborations exist, centering on chronic pain mechanisms, psychiatric depression, and other fields in neuroscience.
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: Christopher Quarles / Kathleen Schmainda / Jerrold Boxerman / Leland Hu
Multi-Site Validation and Application of a Consensus DSC MRI Protocol
The overall goal of this multi-site clinical trial is to validate and demonstrate the clinical utility of a standardized protocol for imaging brain tumor perfusion. Such validation will help to promote widespread adoption of the consensus protocol, thereby improving the reliability of perfusion imaging for response assessment of brain tumor patients in routine neuro-oncology practice and prospective 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.
Lipid Domains in Lens Membranes of a Single Eye: EPR Spin-Labeling Studies
The long-term objective of this proposal is to achieve a greater understanding of the function of cholesterol in fiber cell membranes.
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.
Upgrades to a Bruker Q-band E580 Pulse EPR Spectrometer
The research proposed here, which uses novel state-of-the-art enhancements to a biophysical spectroscopic technique to enable the study of protein structure and functional dynamics, will lead to a better understanding of the physiology of disease processes such as cardiovascular and pulmonary diseases; cystic fibrosis; diabetes; obesity; behavioral, neurological, and psychiatric disorders; Alzheimer’s disease; and cancer. This research will also contribute to the development of novel antibiotics and cancer therapeutic agents, and to the design of safer and more effective drugs targeting a broad spectrum of diseases. Additional avenues of research are expected to be uncovered once the success of the initially proposed projects is evident, fostering further opportunities for new interdisciplinary science.
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.
Molecular Determinants of Drug Sensitivity and Resistance to Gallium-based Therapy in Pediatric Brain Tumors
PI: Kathleen Schmainda
Preclinical Evaluation of Novel Iron-Targeted Therapy for Treatment-Resistant Pediatric Glioblastoma
PI: Kathleen Schmainda
Froedtert Hospital Foundation
Obtaining Preclinical Evidence for a Novel Iron-Targeted Therapy for Glioblastoma