DEVELOPMENT OF IMAGING TECHNOLOGIESMagnetic resonance imaging (MRI)
MRI is a key technology in modern imaging, which due to its versatility covers a broad range of in vivo applications. MRI is characterized by inherently low sensitivity due to the low quantum energy involved. One of the objectives of the lab is to improve the sensitivity defined as the signal-to-noise ratio per unit time.
SNR/t can be increased by either
- increasing the signal → higher magnetic field strengths or hyperpolarization of nuclei,
- decreasing noise, → reducing the noise figure of the detection electronics by cooling
- acceleration →decreasing the acquisition time by reduced k-space sampling
Non-invasive fluorescence imaging utilizes the low tissue absorption in the near-infrared spectral window; in this spectral domain light attenuation by tissue is ~10dB/cm and photons that have traveled several cm might still be detected. Photons are strongly scattered by tissue and light propagation in tissue is described as a diffusive wave. The principal problem in fluorescence imaging is to retrieve spatial information from the diffuse signals detected on the surface. While intrinsic optical imaging analyzes the optical properties of the tissue itself (attenuation, scattering coefficients), fluorescence imaging aims at estimating the distribution and local concentration of an exogenous fluorescent probe.
We are developing a multi-spectral fluorescence tomography system that will allow the three-dimensional reconstruction of a fluorophor distribution in tissue. The system will operate in the non-contact mode, i.e. light source and detectors are not in direct contact with the sample.
High resolution structural imaging of the rodent brain
Exploiting the high sensitivity provided by low temperature detection rodent brain anatomy will be studied at spatial resolutions better than 100μm. High resolution MRI will be applied to characterize structural changes in models of neurodegeneration (e.g. deposition of b-amyloid peptide deposits in the brain of genetically engineered mouse models of Alzheimer’s disease) or of white matter lesions (using magnetization transfer contrast and diffusion tensor imaging)
Functional MRI of the rodent brain
A major focus area is the development and applications of techniques to non-invasively monitor functional activities of the rodent brain. Various fMRI readouts, sensitive to changes in blood oxygen concentration (BOLD contrast), cerebral blood volume (CBV) or flow (CBF), are applied to visualize brain activation in response to sensory Upper row: forepaw stimulation), noxious, physiological or pharma-cological stimulation (lower row: stimulation with 5HT1A agonist). Applications involve various models of CNS disorders such as neurodegeneration, psychiatric diseases, white mater lesions or trauma (spinal cord injury) and studies of functional plasticity in the rodent brain.
Metabolic studies in models of CNS disorders
Metabolic alterations are early indicators of pathological transformation or response to therapy. MR spectroscopy and MR spectroscopic imaging provides a unique window to study metabolic alteration non-invasively. Both single voxel spectroscopy (Figure: 1H MR spectrum of mouse ecerebral cortex) and spectroscopic imaging have been implemented. The methods will be applied to models of neurodegeneration and psychiatric diseases.
SYSTEMS PHYSIOLOGY PROJECTS
Hypoxia inducible factor (HIF) pathway
Structural and functional aberrations are consequences of cellular and molecular events. Hence visualization and quantification of such process would be of high medical interest, enhancing diagnostic relevance and allowing monitoring pathological events and therapeutic interventions at a mechanistic level. Imaging approaches using reporter systems that specifically home-in to a molecular or cellular target are currently developed at a rapid pace. Strategies involve direct probes linking a reporter group to a target-specific ligand, activatable probes that will become detectable only in the presences of the molecular target, and indirect approaches such as the expression of reporter genes. Molecular imaging uses multiple imaging modality, most importantly nuclear and optical (fluorescence and bioluminescence) imaging due to sensitivity reasons. Molecular imaging provides information on receptor expression levels, receptor function, signal transduction pathway activities, cell migration, etc.
Our group is interested in measuring signal transduction pathways such as the signaling cascade initiated by hypoxia. A reporter gene assay expressing red fluorescent protein mutants linked to hypoxia-inducible factor (HIF) has been developed, which should allow monitoring HIF expression non-invasively using fluorescence molecular tomography. HIF induction prompts a cascade of downstream events that can be also be monitored using target-specific and physiological imaging techniques. Once available, the assay will be used to characterize pathological conditions involving hypoxia (e.g. cerebral ischemia, tumor proliferation/ angiogenesis).