Objective
In the past years there has been a considerable progress in unraveling the genetic,basis of numerous hereditary diseases, such as the Huntington disease or Familial adenomatous polyposis. On the other hand, the control of susceptibility to many common diseases including various types of sporadic cancer, infectious, autoimmune and metabolic diseases, etc. remains unknown, in spite of considerable evidence that they are also under genetic control. Unfortunately, in these diseases multiple genes are involved, and hence it has been difficult to map the responsible genes in humans. This has led to an increased interest in genetics of animal models of these diseases.
The dissection of complex traits remains a difficult task, in spite of availability of very large numbers of microsatellite probes. The task is even more confounded by our discovery of frequent inter-locus interactions which tend to obscure the individual effects of the genes involved. To facilitate the mapping, the laboratory of the proposer developed a novel genetic system, the Recombinant Congenic Strains of mice (RCS), which transforms the multigenic difference between two strains into sets of oligogenic or single-gene differences, which are easier to dissect. The RC strains increase the genetic resolution by a. increasing the chance of obtaining a high statistics of linkage for a QTL b. requiring a less stringent multiple-test correction of this result and c. increasing the probability of detecting interactions between non-linked QTLs. In the past period a series of collaborative efforts using the RCS led to mapping of a number of tumor susceptibility genes, genes controlling various steps of T Lymphocyte activation, susceptibility to apoptosis, infectious diseases and defects of lipid metabolism. These data show the power of the system and its general applicability to a variety of functions and diseases. As the potential for and interest in the use of the RCS increases, the capacity of the laboratory as well as the logistics of distribution are becoming inadequate in providing sufficient and timely supply of these mice to all interested. Moreover, there is a need to upgrade the microbiological quality of these mice and to secure this unique genetic tool by cryopreservation. Therefore, we propose to establish an RCS facility which would increase the microbiological quality of these mice and make the strains easily accessible to European scientists. The strains will be also cryopreserved. When this task is completed, the facility of a high quality could be maintained at a yearly cost of approximately 135,000 ECU.
The second part of the project provides an important component to the current disease-gene mapping programme: the analysis of the genetics of susceptibility to the rheumatoid arthritis (RA). This disease occurs with a high frequency in Western countries and due to lack of efficient treatment leads to inevitable invalidity and increased mortality. The role of inflammatory processes and the involvement of cytokines in RA make its study complementary to the other current projects (mapping of genes regulating cytokine production and response, resistance to infectious diseases, genetics of inflammatory bowel disease). In the past, the role of the MHC class ll in RA has been established. However, the role of the rest of the genome remains unknown. We shall use the series of MHC identical OcB/Dem RC strains which exhibit large differences in a number of immunological parameters to study the genes controlling susceptibility to collagen-induced arthritis in mice, in presence and in absence of a susceptible H2 haplotype. The non-MHC susceptibility genes will be mapped with a precision which would allow to locate their human homologues. The interactions of these genes and their functional impact on the immuno-pathology of the disease will be tested and the results compared with those obtained in other models to obtain a more general image of the genetic control of normal and aberrant immune response.
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.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesclinical medicinerheumatology
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesbasic medicineneurologydementia
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Topic(s)
Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
1066 CX Amsterdam
Netherlands