In the Department of Biophysics, scientists use physical science methods to study biological systems. Specifically, our research is focused in the areas of electron paramagnetic resonance (EPR), magnetic resonance (MR) physics and brain imaging, and redox research.
The Department of Biophysics is home to the National Biomedical EPR Center (a national P41 Research Resource supported by the NIH/NIBIB), which is the most extensive EPR facility in the nation. The research conducted within the EPR Center includes technological innovation and application of new techniques to biological problems. The main areas of research 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 MR (magnetic resonance) 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 fMRI in 1992 and on resting-state functional MRI (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.
Scientists in the Department of Biophysics are internationally recognized for their expertise and contribution to the field of free radical and redox biology. The main research focus is on establishing the role of free radicals and oxidants in pathophysiological conditions (e.g., in cardiovascular diseases, neurodegeneration, and cancer) and in normal cell function. The department provides an environment conducive to the development of novel, rigorous chemical probes and assays for monitoring the generation of free radicals in cells (in vitro) and in animals (in vivo). These include fluorogenic and bioluminescent probes, EPR spin traps, and probe-free assays (e.g., redox immunoblotting [peroxiredoxins, thioredoxins] and low-temperature EPR studies of the redox status of cellular protein metal centers). Ongoing collaborative work within MCW (e.g., Cardiovascular Center, Cancer Center) and with other institutions utilizes these assays to understand the role of oxidants in cardiovascular diseases (e.g., stroke, ischemia-reperfusion), neurodegeneration (e.g., Parkinson Disease), and cancer (e.g., cancer cell proliferation, chemoprevention, and chemotherapy).
Our faculty are supported by internal and external funding sources, including the National Institutes of Health.
National Biomedical EPR Center
The mission of the EPR Center is to serve the community of EPR spectroscopists by development of advanced EPR instrumentation and new EPR methodology.
*Named PI & director on 01/06/16 upon retirement of James Hyde, original PI
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.
CYP2E1 Mediated Mitochondrial Injury and Cell Damage in Alcohol Liver Disease
A major objective is to investigate the mechanisms of alcohol induced mitochondrial dysfunction and develop antioxidants and enzyme inhibitors to minimize alcohol induced liver damage.
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.
Cholesterol Crystalline Domain Function in Eye Lens: 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.
LptA-Mediated Transport of LPS
The proposed studies focus on how the periplasmic protein LptA receives LPS from the IM-associated protein LptC, how LptA protects the hydrophobic acyl chains of LPS as it crosses the periplasm, and how LptA delivers LPS to LptDE at the OM. Genetic screenings, laser light scattering analyses, EPR spectroscopy studies, and isothermal titration calorimetry (ITC) measurements will provide detailed insights into the mechanism of LPS transport across the periplasm of Gram-negative bacteria.
Mechanism of Activation and Membrane Interactions of Pseudomonas Toxin ExoU
In this project biochemical and biophysical studies will be used to elucidate the molecular mechanism of activation for the phospholipase ExoU, with a long term goal of facilitating the development of novel inhibitors to reduce tissue damage or sepsis due to P. aeruginosa infection.
Tetrahydrobiopterin in Fetal Hypoxia Brain Injury
The major goals of this project are to investigate mechanisms of neuronal dysfunction associated with loss of BH4 in antenatal hypoxia-ischemia (HI) at a premature gestation. Using surrogate markers of magnetic resonance imaging this proposal, will study neuronal cell responses in the early critical phase of injury, which seems to determine the eventual course of events leading to movement disorders of cerebral palsy.
Network-Level Mechanisms for Preclinical Alzheimer’s Disease Development
The overall goal of this project is to determine whether, during the preclinical Alzheimer’s disease developmental phase in CN older subjects with the apolipoprotein ε4 allele, decreased abnormal hyperfunctional connectivity can be correlated with improved episodic memory using a perturbation, such as a low dose of levetiracetam.
Diversity Summer Health Research Education Program
Undergraduate Training grant to increase the diversity force in medical research.
Targeting Pancreatic Cancer Energy Metabolism, Tumor Growth, and Metastasis
The overall goal of this project is to develop new therapeutic approaches to inhibit PDAC malignancy.
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.
MPI: Shi-Jiang Li / Barbara Bendlin
Alzheimer’s Disease Connectome Project
The long-term goal of this project is to apply the Human Connectome Project (HCP) data collection protocol and develop robust technology to accurately stage AD across the full spectrum of its progression on an individual subject basis.
PI: Jacek Zielonka
MCW Cancer Center
Targeting Mitochondria with Redox Cycling Agents to Overcome Drug Resistance in Human Colon Cancer Cells
Resistance of cancer cells to chemotherapy is an important factor leading to poor prognosis of cancer patients, despite the impressive advances in the anticancer therapeutic strategies over the last 20 years. Drug-resistant cells rewire their metabolism network, often with increased reliance on mitochondria to produce energy. We will design, synthesize, and evaluate the antiproliferative and cytotoxic potential of new redox cycling agents targeted to cancer cell mitochondria, in wild-type and drug-resistant colon cancer cells. These compounds are designed to inhibit mitochondrial respiration and induce oxidant stress in cancer cells. At the conclusion of these studies, we will have determined the potential of targeting redox-active drugs to mitochondria to inhibit proliferation and kill drug-resistant cancer cells.
PI: Kathleen Schmainda
Froedtert Hospital Foundation
Obtaining Preclinical Evidence for a Novel Iron-Targeted Therapy for Glioblastoma
PI: Michael Lerch
Molecular Mechanisms of Endogeneous Modulators of Beta2-Adrenergic Receptor Signal Transduction