Objective
Research objectives and content
Regarding the work proposed here, we we further investigate the network and cellular interactions involved in the early formation and patterning of the mid-/hindbrain junction as well as in the specification of mesencephalic, dopaminergic and serotoninergic neurons. We shall investigate specifically the role of Otx-2 and En-1 in brain pattern formation using gain-of function experiments.
The principal aims of the present proposal are:
Objectives:
a) to characterize the role of Otx-2 in midbrain specification as well as in mid-/hindbrain border formation by ectopic expression using the En-1 promoter, b) to explore the role of Engrailed in mid-/hindbrain specification, in mesencephalic dopaminergic neurons induction and for maintenance using Otx-l promoter. In order to elucidate the function of the homeobox gene Otx-2 in the mid-/hindbrain formation, we intend to aberrently express the gene in the mes-metencephalic domain by a gain-of-function approach.
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Therefore, we would like to shift Otx-2 expression caudally into the metencephalon. To achieve this goal, we will use a knock-in approach. We will replace the En-1 gene with a Otx-2 minigene by homologues recombination, therefore, Otx-2 will be under the control of En-1 regulatory elements. Using this strategy, the Otx-2 expression domain will be shifted caudally into rhombomere 1. Similarly, we will use the knock-in approach using the Otx-1 locus as a target to drive the En-1 gene. By expressing En-1 under the control of Otx-1, we will shift En-1 expression from the mesencephalon into the prosencephalon. This experiment is designed to tell us whether En-1 is necessary for pattern-inducing formation of the mesencephalon.
Training content (objective benefit and expected impact)
The proposed research and training will impact several areas. First, we will learn whether Otx-2 plays an instrumental role in forming the mid-/hindbrain organizer. Second, we will learn whether Engrailed plays a role in mesencephalon pattern formation and whether En-1 also plays a role in the induction and differentiation of dopaminergic neurons. These results could have some clinical impact because in patients with Parkinson's disease, dopaminergic midbrain neurons degenerate slowly and it is possible that Engrailed is one of the factors which might be involved in differentiation or maintenance of these cells. Moreover, I will have the opportunity to learn modern embryological technologies which are crucial for generating gain-of-function and loss-of-function experiments. After this training period, I will be able to transfer this technology to my Home Institute in Spain which will enable me to perform similar experiments independently in the future.
Links with industry / industrial relevance (22)
At present, there are no links with industrial partners, however, it could be of relevance in the near future, if our results indicated that Engrailed might play a role in induction and maintenance of dopaminergic neurons. If this is the case, we will contact industrial partners.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
85764 Neuherberg
Germany
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