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Can DPP-IV (Dipeptidyl peptidase -4) inhibitors prevent retinal neurodegeneration and blood-retinal barrier breakdown in multiple sclerosis?
Portugal (PorMSIC) - University of Coimbra, Coimbra
iCBR – Coimbra Institute for Clinical and Biomedical Research
António Francisco Ambrósio
Rosa Cristina Simões Fernandes
Type of Research Project
- Basic science
What is the background of the project?
Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS) and one of the most highly system susceptible to damage is the visual system. Our group has previously reported that incretin-based therapies could prevent the increased blood-retinal barrier permeability in a model of type 1 diabetes and retinal injury by ischemia-reperfusion (IR). Furthermore, we showed that the beneficial effects of a GLP-1 (glucagon-like peptide) receptor agonist (Exendin-4) in preventing IR injury–induced breakdown and inflammation were mediated through inhibition of inflammatory cytokine production by activated microglia. These findings suggest that incretin-based therapies could be a promising option in treating diseases involving retinal inflammation.
What is the aim of the project?
The aim is to clarify whether GLP-1 (glucagon-like peptide 1), one of the main substrates of DPP-4 (Dipeptidyl peptidase -4), has protective effects on the retina of an animal model with Multiple sclerosis (cuprizone (CPZ) induced demyelination mouse model), by using a DPP-4 inhibitor (sitagliptin).
What techniques and methods are used?
The project will make use of two major techniques: immunohistochemistry and western blotting. Western blotting results will be analyzed through a densitometer and complemented with imaging software to compare the signal generated by the bands detected. With immunohistochemistry we will be able to analyze the interaction between the protein and the components of the retina. With this two techniques we believe we will be able to assess if GLP-1 (glucagon-like peptide 1) has protective effects on the retina of an animal model with MS.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
It is expected that the student will acquire knowledge in the field of the research project, learning about retinal dysfunction in multiple sclerosis and pleiotropic effects of incretin-based therapies. It is expected that the student will have the opportunity to contact and perform some basic lab methodologies, including Western Blotting and immunohistochemistry, improving his practical skills.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
At the beginning of the internship, the tutor will present the project. Some preliminary readings are mentioned at the end.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
It is expected that the student has good social interaction and be able to collaborate with the group members. It is expected that the student has critical thinking and problem solving skills.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- Protective effect of a GLP-1 analog on ischemia-reperfusion induced blood-retina barrier breakdown and inflammation. A. Gonçalves; A. Muthusamy; C.-M. Lin; C.F. Ribeiro; A.F. Ambrósio; S.F. Abcouwer; R. Fernandes and D.A. Antonetti. Invest Ophthalmol Vis Sci; 2016; 57:2584-92. (doi: 10.1167/iovs.15-19006).
- Dipeptidyl peptidase-IV inhibition prevents blood-retinal barrier breakdown; inflammation and neuronal cell death in the retina of type 1 diabetic rats. Gonçalves A; Marques C; Leal E; Ribeiro CF; Reis F; Ambrósio AF; Fernandes R. Biochim Biophys Acta. 2014 Sep;1842(9):1454-63. (doi: 10.1016/j.bbadis.2014.04.013)
- Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model. Gonçalves A; Leal E; Paiva A; Teixeira Lemos E; Teixeira F; Ribeiro CF; Reis F; Ambrósio AF; Fernandes R. Diabetes Obes Metab. 2012 May;14(5):454-63 (doi: 10.1111/j.1463-1326.2011.01548.x)
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