Objective
Genetically modified mice are of considerable value for understanding the molecular basis of human disease and for the development of new diagnostic and therapeutic approaches. In this project we propose to construct transgenic mice which will serve as mode/e for tumourigenesis, or for human developmental disorders.
First generation transgenics did not mimic a "natural" mutational event, because of the effect of random integration of the transgene, the use of heterologous promoters, and the presence of two non-mutated endogenous alleles. Similarly, first generation knock-outs were mostly aimed at obtaining a complete loss of function of the targeted gene, often resulting in non-informative early lethal phenotypes.
The approach described in this project is a substantial step forward with respect to the above techniques, since it is aimed at obtaining mice bearing the exact replicas of naturally occurring genetic lesions in man. We will activate (or partially inactivate) genes by introducing point mutations in the targeted sequence by homologous recombination, without perturbing the endogenous pattern of expression. The targets will be four receptor tyrosine kineses (RTKs) known for their oncogenic potential, and for being involved in development Met, Ret, PDGFR, and Trk.
The introduction of gain of function mutations in receptor genes should induce the appearance of a variety of tumors in the transgenic animals (oncomice). Such oncomice will be, first of all, of diagnostic va/ue, since the development of tumors in specific tissues will pinpoint the cell types susceptible to oncogenic transformation for each receptor. Furthermore, they will make it possible to explore in-vivo the multi-step nature of tumourigenesis, for example by testing the effect of the mutation in different mouse strains, or by crossing the mice with transgenics carrying inactivating mutations in tumor suppressor genes. Finally, these animals will represent ideal tools to test the efficacy of a family of anti-cancer drugs currently being developed by pharmacological industries, based on the inhibition of tyrosine kinase activity or signal transduction.
The loss of function mutations are likely to yield a phenotype in the heterozygous condition, due the dominant negative effect caused by receptor dimerization. The defects of these animals should be milder than those found in the corresponding knock-outs (embryonal or perinatal lethal for Met, Ret, and PDGFR). Such partial loss of function phenotypes may thus provide additional information with respect to the knock-out, and may help linking a partial loss of function of Met and PDGFR (for which,at present, there no corresponding pathology) with human developmental disorders.
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.
- natural sciences biological sciences genetics mutation
- medical and health sciences basic medicine pathology
- natural sciences biological sciences genetics genomes
You need to log in or register to use this function
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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.
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.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Data not available
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Funding Scheme
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.
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
10126 Torino
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.