Miniprojects

Eestikeelse lisainformatsiooni saamiseks vajuta siia.

In the University of Iceland, for visiting University of Tartu medical undergraduates

Dr Þór Eysteinsson

Faculty of Medicine, School of Health Sciences, University of Iceland

Topics 1-4: Kabuki syndrome is an autosomal dominant disorder that results from heterozygous, typically de novo, inactivating mutations in KMT2D. This is an enzyme that normally catalyses histone methylation on H3 at lysine 4 (H3K4me). Individuals with Kabuki syndrome 1 (KS1) exhibit postnatal growth retardation, intellectual disability, and hearing deficits and craniofacial abnormalities (Wang et al. 2018). In addition, ocular abnormalities are observed (Chen et al. 2014; Kim, Kim, and Hwang 2011), and patients with Kabuki syndrome show hearing impairment that affects speech and language (Morgan et al. 2015).

        1. Electrophysiological assessment of retinal and visual function in a mouse models of Kabuki syndrome, with electroretinogram (ERG) and visual evoked potential (VEP) recordings.
Undergraduate will measure the scotopic and photopic ERG responses and the VEP using different mouse models of Kabuki syndrome.

        2. Behavioral and functional testing of auditory function in a mouse model of Kabuki syndrome.
Undergraduate will examine auditory function in mouse models of Kabuki syndrome using brainstem recordings and behavioural testing.

        3. Fundus photography, fluorescent angiography of retinal vasculature, examination of retinal layers and thickness, and optic nerve integrity by optical coherence tomography (OCT) in a mouse model of Kabuki syndrome.
Undergraduate will obtain fundus and OCT images of the retinae of a mouse model of Kabuki syndrome, and assess all relevant parameters pertaining to retinal thickness, in particular the inner and outer layers, optic disk anatomy, fundus pigmentation and structure of the retinal vasculature, the last by means of fluorescent angiography.

        4. Assessment of structural changes in the retina and retinal pigment epithelium (RPE) of “flat mounts” of these ocular structures from a mouse model of Kabuki syndrome.
Undergraduate will use the retinal and RPE “flat mount” preparations, and confocal microscopy to examine autofluorescence as indication of lipofuscin accumulation, and markers such as phalloidin and Z-occludin to examine the integrity of the RPE.

Topic 5: Wolfram syndrome is a rare autosomal recessive disorder caused primarily by mutations within the Woframin (WFS1) gene. Patients show very early optic atrophy and diabetes mellitus, and unfortunately the disease prognosis is poor (Urano 2016). Retinal nerve fibre layer (RNFL) thinning is observed, and there are subtle changes found in the ERG and VEP responses, leading to reduced visual acuity and visual function, although the exact cause is still unclear (Scaramuzzi et al. 2019; Soares et al. 2019).

        5. Assessment of structural changes in the retina and retinal pigment epithelium (RPE) of “flat mounts” of these ocular structures from a mouse model of Wolfram syndrome.
Undergraduate will use the retinal and RPE “flat mount” preparations, and confocal microscopy to examine autofluorescence as indication of lipofuscin accumulation, and markers such as phalloidin and Z-occludin to examine the integrity of the RPE.
 

In the University of Tartu, for visiting University of Iceland medical undergraduates

Dr Miriam A Hickey, Dr. Monika Jürgenson

Department of Pharmacology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu

Topics 6-7: In order to be fluorescent, a molecule absorbs energy (for example light), reaches an excited state and then emits a photon (the fluorescence) and returns to ground state. Living tissues contain molecules that emit fluorescence (Croce and Bottiroli 2014). Some of these fluorophores (fluorescent molecules) are important for mitochondrial health and they can be identified based on their fluorescence lifetime, which is the time that the fluorophore spends in the excited state before it emits a photon and returns to ground state. Using our unique in vivo fluorescence lifetime imager, we can examine mitochondrial status in mouse models of neurodegenerative disease.

        6. Optical in vivo imaging of endogenous fluorophores in a mouse model of Wolfram syndrome.
Undergraduate will study whether endogenous fluorophores are altered in brain in a mouse model of Wolfram syndrome, which displays profound mitochondrial impairment (Cagalinec et al. 2016).

        7. Optical in vivo imaging of endogenous fluorophores in a mouse model of Alzheimer’s disease.
Undergraduate will examine fluorescence intensity and fluorescence lifetimes of endogenous fluorophores in brain by using a mouse model of Alzheimer’s disease, which also causes profoundly impaired mitochondrial function (Kerr et al. 2017).

Topics 8-10: Sensory neuropathy is highly prevalent in Parkinson’s disease (PD) (Terkelsen et al. 2017); however, the pathophysiology underlying this deficit remains unclear. For example, we have previously shown that mitochondrial function and recycling is impaired in PD (Choubey et al. 2011); however, mitochondrial function in sensory neurons in PD has been little studied. We will also examine calcium signalling in primary sensory neurons, which is a sensitive indicator of excitability and neuronal activity (Grienberger and Konnerth 2012). Sensory neuropathy may result from degeneration of terminals of sensory fibres but it can also be caused by enhanced excitability without degeneration (Terkelsen et al. 2017); thus, we will examine morphology of developing sensory neurons.

        8. Calcium signalling in a sensory neuronal cell model of Parkinson’s disease.
Undergraduate will prepare primary sensory neurons from models of Parkinson’s disease, examine calcium signalling in these neurons and compare their activity to control neurons.

        9. Mitochondrial dynamics (mitophagy, fusion and fission) in a sensory neuronal cell culture model of Parkinson’s disease (PD).
Undergraduate will prepare primary sensory neurons from models of Parkinson’s disease and will examine mitochondrial recycling, and fusion and division in these neurons and compare to control neurons.

        10. Morphological analysis of dorsal root ganglia as models of Parkinson’s disease.
Undergraduate will examine morphology of neurons modelling Parkinson’s disease over time, in comparison to control neurons.

Topics 11-14: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the elderly and unfortunately, the disease is incurable and the treatments remain capable of addressing symptoms only. Given the extensive pathology present at diagnosis, earlier diagnosis is critical to enable earlier implementation of treatments. Deficits in vision are an early marker of Alzheimer’s disease (Kirby, Bandelow, and Hogervorst 2010) and the retina shows evidence of degeneration (Hart et al. 2016) and here, we aim to examine visual function in a mouse model of AD.
Better treatments that address ongoing neurodegeneration in AD are also required. Towards this end, undergraduates will have an opportunity to become involved in ongoing preclinical trials on a mouse model of AD. We have previously shown cognitive deficits in a mouse model of Alzheimer’s disease (Enevoldsen et al. 2012; Jürgenson, Aonurm-Helm, and Zharkovsky 2012) and we will utilize these tasks to assess the efficacy of our treatment. We will also assess whether our treatment affects circadian rhythm, as patients with Alzheimer’s disease have abnormal sleep-wake cycles and this disruption to their circadian rhythm plays a role in the progression of their disease (Saeed and Abbott 2017). Finally, several deficits are observed in AD patients when imaged using diffusion tensor imaging (DTI) (Kantarci et al. 2017), which is a sensitive imaging technique that enable visualization of neuronal integrity and fibre tracts.

        11. Visual function in a mouse model of Alzheimer’s disease (AD).
Undergraduate will examine visual acuity (accuracy) in a mouse model of AD using a novel highly sensitive automated test (OptoMotry).

        12. Behavioural (cognitive) analysis of a mouse model of Alzheimer’s disease.
Undergraduate will take part in an ongoing preclinical trial to assess cognitive function in a mouse model of Alzheimer’s disease following intervention.

        13. Detailed analysis of circadian rhythm in a mouse model of Alzheimer’s disease.
Undergraduate will take part in an ongoing preclinical trial to assess circadian rhythm in a mouse model of Alzheimer’s disease following intervention.

        14. Diffusion tensor imaging (DTI) in a mouse model of Alzheimer’s disease.
Undergraduate will examine integrity of fibre tracts in brain during early disease progression in a mouse model of AD.

NB! We understand that science changes fast and that the miniproject topics may change slightly over time as more information emerges from each!