For masters students in physics, biophysics, biomedical engineering, chemistry, biochemistry and biology, we offer a stimulating research environment with interesting projects to work on.
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∗ Chemical exchange saturation transfer (CEST) ∗
A) Of new compounds for tissue targeted contrast
B) Of the human pancreas
Background: CEST is a new MR contrast method, making use of irradiation of protons on compounds exchangeable with water protons. In this way the sensitivity of imaging these compounds can be increased considerably. In collaboration with the TU Twente several functionalized polymers (e.g. drug carrying, targeted to tissue receptors etc) will be produced with water exchangeable protons.
Detection of tumors in the pancreas is problematic. This tissue is rich in proteins with exchangeable polyamide protons and thus may show good CEST contrast, which can used to detect tumor tissue. We obtained a work-in-progress (WIP) from Siemens to be tested on patients .
Aim: a. To test the CEST potential of various amide, imine and amino polymers synthesized in collaboration with TU Twente, both in vitro and in vivo (tumor tissue targeting).
b. To apply a CEST WIP package of Siemens on human pancreas (volunteers & patients).
Methods and supervision: a. Can be performed on the 7T Clinscan. b) on the 3T Trio. The WIP has been installed on both systems and two PhD students are involved in this work.
Contact: Arend Heerschap
∗ Effect of energy stimulating compounds on cerebral blood flow in mice ∗
Background: We recently discovered profound effects of creatine on various body functions in mice including blood flow in the brain (measured by arterial spin labeling). These effects may be important to understand widely used fMRI studies in which blood flow changes are key events. Confirmation of these results is needed in creatine deficient mice which are fed with creatine. Homoarginine is compound known to protect the brain against infarctions. We want to test if homoarginine affects blood flow in the brain. Resveratrol has been identified as the “health active” compound in red wine and appears to increase blood flow.
Aim: To determine the effects of creatine, homoarginine and resveratrol on cerebral blood flow by arterial spin labeling (ASL) in MR
Methods and supervision: mice deficient in creatine, wild type mice and Alzheimer model mice will be the animals involved in this study. ASL acquisition and processing is operational on the 11.7T Biospec. An animal license course might be part of this project. PhD students & postdoc work on these projects. The use of special 13C MR spectroscopy techniques may be part of this project to characterize certain physiological and metabolic functions.
Contact: Arend Heerschap
∗ MR imaging of zebrafish ∗
Background: Zebrafish are becoming important as animal species in biomedical research e.g. for brain, cancer and cardiac applications. As they spontaneously renew their heart after injury it is of interest to investigate how this regeneration takes place as a model for potential human heart regeneration after heart attacks. We developed a unique setup for zebrafish imaging on a 11.7T MR system and demonstrated that ultra-high resolution imaging is possible, together with a research group in Madrid, specialized in zebrafish studies. For useful imaging of damaged zebrafish heart cardiac triggering and ultra-short echo-times to visualize collagen formation are required.
Aim: To realize imaging of zebrafish, in particular moving damaged heart.
Methods and supervision: zebrafish will be obtained from the department Animal Physiology. Cardiac triggering and ultra-short TE imaging are available on our 11.7T system. An animal license course and visit to the Madrid group to learn handling zebrafish will be part of this project. The MR operator who built the zebrafish probe at 11.7T and PhD students will be involved.
Contact: Arend Heerschap
∗ 31P and 1H MR spectroscopic imaging of brain tumors. ∗
Background: An important class of glioma brain tumors a mutation leading to specific metabolic alterations (biomarkers) detectable by MR spectroscopic imaging. We want to explore treatments of these brain tumors by targeting this metabolic pathway and therefore need to further characterize it with new 13C MR spectroscopy methods to determine metabolic fluxes. We want to explore the MR biomarkers to identify these class of brain tumor patients without the need for a brain operation.
Aim: To determine metabolic fluxes in mice models for specific brain tumor. To perform 31P and 1H MR spectroscopic imaging of human brain tumor patients with the specific mutation.
Methods and supervision: in collaboration with the department of Pathology there are several brain tumor models in mice available for these studies. Experiments can be performed on either 7T or 11.7T MR systems. Human studies will be done on the 3T TRIO clinical scanner together with technician and postdoc. MR hard and software for these studies is available. If interested the student may work on special MR spectroscopic methods to detect new biomarkers. Supervision by postdoc and PhDs.
Contact: Arend Heerschap
∗ Hepatic ATP resynthesis upon fructose load: A window on hepatic mitochondrial function. ∗
It’s well known that obesity related diseases as Type 2 diabetes and non-alcoholic fatty liver diseases result from an energetic imbalance within insulin responsive tissues. The mitochondria is responsible to maintain energy homeostasis by promoting or inhibiting substrate oxidations/synthesis according with extra or intracellular needs. It is thought that during the development of hepatic insulin resistance (the tissue does not respond to insulin), mitochondrial dysfunction occurs due to inability to oxidize the constant fatty acid overload. This will ultimately lead to the accumulation of intermediary lipid species, which were not fully oxidize and those serve as signaling molecules interfering with insulin signaling pathway and interrupt insulin mediated glucose oxidation. Therefore we aim to develop a method to assess hepatic mitochondrial oxidative capacity in vivo in mice with 31P magnetic resonance spectroscopy (MRS). For this purpose we will deplete ATP with an intravenous bolus of fructose and we follow its resynthesis as measure of hepatic mitochondrial oxidative capacity. To validate the technique, we plan to manipulate hepatic mitochondrial function with synthetic drugs as AICAR (a promoter of substrate oxidation through activation of AMPK) and if possible with an high fat diet.
When fructose is oxidized, it bypasses intracellular ATP control and quickly leads to ATP depletion and phosphomonoester increases, particularly fructose-1-phosphate. This ATP depletion promotes AMPK activation which in turn stimulates maximum mitochondrial oxidative capacity to replenish ATP levels. These high energy phosphates can be observed in vivo with 31P MRS at 7T and/or 11.7T.
Contact: Arend Heerschap
∗ In vivo skeletal muscle fatty acid oxidation with 13C MRS ∗
Skeletal muscle is an insulin responsive tissue and therefore plays an important role in the development of insulin resistance and type 2 diabetes. It is primordial that this tissue adapts his oxidative machinery to handle the constant deliver of fatty acids. A poorly adjusted mitochondrial β-oxidation activity dictates the accumulation of those fatty acids within the intramyocellular pool, driving deleterious effects to insulin signalling pathway and glucose oxidation.
Our aim is to develop a method to assess in vivo fatty acid oxidation in skeletal muscle of mice using stable isotope fatty acids at 11.7T.
These 13C enriched fatty acids are infused in the mice and once inside the myocytes they undergo β-oxidation and tricarboxylic acid cycle pathways, spreading the 13C labelling through their oxidative route. These 13C enriched products, like glutamate, can be detected by 13C MRS and their label pattern is a direct measure of fatty acid oxidation, with more 13C enrichment being a sign of more 13C labelled fatty acids oxidized. Complete resolution of 13C glutamate species will allow us to determine how much of the a given fatty acid underwent fully oxidation. This method opens a new breakthrough to assess whether a skeletal muscle from an obese mouse, for instance, still has the ability to completely oxidize overflow of fatty acids.
Contact: Arend Heerschap