2013 CBIS Seed Grant Recipients
May Han, MD,
Michael Zeineh, MD-PhD
Neurology and Radiology
Project: Imaging Inflammatory Activity in Multiple Sclerosis using Ferumoxyol-Enhanced Ultra High Field MRI
We hypothesize that the combination of very high resolution anatomical imaging and cellular/molecular imaging using intravenously injected iron oxide nanoparticles, obtained with clinically relevant protocols at ultra high field (UHF) magnetic resonance imaging (MRI), will provide the first in vivo evidence for active inflammation within cortical and adjacent meningeal tissue in early multiple sclerosis (MS) patients. Specifically, we will perform scanning during an active phase of MS at 7T, comparing conventional gadolinium with novel iron oxide imaging in order to assess for clinically relevant changes in cortical, subcortical, and deep gray inflammation.
Project: Coma, Consciousness and Connectivity: Using Novel Methods of Functional Brain Imaging to Predict Outcome in Comatose Survivors of Cardiac Arrest
During a cardiac arrest, the heart provides inadequate blood flow to the brain, causing significant neurological damage. Survivors of cardiac arrest often remain acutely comatose and face a prolonged recovery, with some returning to meaningful function and many others being left with devastating brain damage. Near infrared spectroscopy (NIRS) is a non-invasive, bedside methodology that uses infrared light to image cerebral oxygenation and cerebral blood flow. By comparing regions that are active at the same time, NIRS can also be used to determine functional connectivity within brain networks (so called “functional NIRS”). This study will use functional NIRS to image brain network connections in comatose survivors of cardiac arrest and determine if the degree of connectivity in specific brain networks, especially those networks implicated in consciousness generation, predicts coma emergence and long-term functional outcome.
Y Joyce Liao, MD-PhD,
Brian Wandell, PhD
Ophthalmology and Pyschology
Project: In Vivo Imaging of Axonal Transport in the Visual Pathway Using Manganese-Enhanced Magnetic Resonance Imaging
Axons are the information highways that connect the 100 billion neurons and form the 100 trillion synapses in the human brain. These brain connections are lost as part of normal aging. The potential causes of such age-dependent loss include impaired axonal transport at the optic nerve head, mitochondrial dysfunction, atherosclerosis, and biomechanical damage. Compatible with this age-related vulnerability, anterior ischemic optic neuropathy, the most common acute optic nerve damage in patients older than 50 years old, and glaucoma, the most common chronic optic neuropathy in the world, predominantly occur in older adults. In this project, we will develop manganese-enhanced magnetic resonance imaging (MRI) as a tool to study axonal transport in the central nervous system in vivo. The paramagnetic dye manganese chloride is injected intravitreally, taken up into the retinal ganglion cells, and transported anterogradely down the optic nerve axons to the superior colliculus (SC) and the lateral geniculate nucleus (LGN) in an activity-dependent manner. This technique will allow characterization of the functional and anatomical properties of the visual pathway in the normal murine visual pathway and following experimental anterior ischemic optic neuropathy (AION). We will also correlate MRI data with changes seen using in vivo retinal imaging techniques including confocal laser scanning ophthalmoscopy and spectral-domain optical coherence tomography.
Molecular and Cellular Physiology
Project: High Resolution Imaging of Intestinal Stem Cell Divisions in Live Adult Drosophila
Stem cells renew adult organs by dividing asymmetrically to produce a stem cell and a cell fated to differentiate. In addition, stem cells can divide symmetrically to produce two stem cells, which enables turnover within the resident stem cell population. Symmetric and asymmetric divisions likely involve distinct cytoskeletal dynamics and cell movements. However, stem cells often live deep within internal organs, creating technical challenges for real time imaging of stem cell divisions in vivo. The adult Drosophila midgut, a new invertebrate model for stem cell renewal, offers a promising alternative to mammalian organs. Analogous to the vertebrate intestinal tract, the Drosophila midgut is a simple and tractable organ whose stem cells are readily visualized in situ by confocal microscopy. Here, we propose to develop methodology for live, high-resolution imaging of Drosophila intestinal stem cells in their native tissue context. The ability to observe symmetric and asymmetric divisions in real time will allow us to address fundamental questions about regulation of stem cell divisions and daughter cell fates.
Live imaging strategy for Drosophila intestinal stem cells. (Left) Midguts will be exposed in live, intact animals in the presence of culture media. (Middle and Right) Fluorescent markers will be used to outline both stem cells and differentiated cells and to visualize their nuclei.
Guillem Pratx, PhD
Project: Do Cancer Stem Cells Accumulate Fluorodeoxyglucose?
Changes in metabolism are one of the hallmarks of cancer and cells in many types of cancers preferentially undergo glycolysis. However, most studies in this area have focused on bulk populations of cancer cells. There is an increasing awareness that cells within the same tumor can be highly heterogeneous in terms of morphology, gene expression and metabolism. This may be due in part to the existence of cellular hierarchies that include cancer stem cells (CSC) and non-tumorgenic cancer cells (NTCs). Interestingly, relatively little is known about the metabolic properties of CSCs as compared to NTCs. Because CSCs contain lower levels of reactive oxygen species (a product of oxidative phosphorylation), we hypothesize that CSCs may be more glycolytic than NTCs and should display higher uptake of fluorodeoxyglucose (FDG), a glucose analogue used for positron emission tomography (PET). To test our hypothesis, we will image the dynamic uptake of FDG in single living cancer cells using a new imaging technique called radioluminescence microscopy, which is unique in its ability to probe radiotracer uptake in a single living cell. This approach should provide far more detailed information than bulk analyses on the metabolism of single cells in a heterogeneous population.
Example of radioluminescence image, showing uptake of FDG in breast cancer cells (MDA-MB-231, 1 h incubration, 250 μCi/mL). The scalebar is 200 μm. FDG uptake is heterogeneous among single cancer cells