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Genetics of normal and abnormal differentiation

Research project P4/17 (Research action P4)

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This project aims to study important aspects of the genetics of normal and pathological differentiation. Use will be made of various models of constitutive or acquired diseases due to certain genetic mutations. This work requires collaboration of laboratories with expertise in biochemistry, cell biology, immunology, and genetics.

The study of constitutional disorders includes Mendelian as well as syndromal and multifactorial diseases, involving both genes directly responsible for the diseases and genes whose activity is modulated by other genes or by epigenetic factors. In the area of Mendelian disorders, we have chosen to characterise the primary defect(s) involved in type-1 carbohydrate-deficient glycoprotein syndrome. This disease is the focus of fruitful collaboration between two of the participating teams: several distinct enzymes may be involved and the multisystemic character of the disorder defies our understanding of gene function. Other inborn errors of metabolism will also be studied, such as adenylosuccinate lyase deficiency and deficiencies in serine biosynthesis, recently described by project participants. As for multifactorial disorders, the focus will be the genetic basis of some forms of diabetes and the association of insulin-dependent and non-insulin-dependent diabetes mellitus, multiple sclerosis, schizophrenia, rheumatoid arthritis, and hypertension, with HLA class II polymorphism and with T-cell receptor, TAP1 and TAP2 transporter, and TNF-beta polymorphism. The project also includes research on a gene involved in multicystic renal dysplasia and obstruction of the pelvi-ureteric junction.

In each case two strategies will be adopted, sometimes concurrently: the bottom-upward approach (aberrant function -> aberrant protein -> mutant gene -> human genome and comparative genome analysis) and the top-downward approach (genome -> gene structure -> protein function plus role in the whole organism).

In acquired diseases, the focus will be benign and malignant cell proliferations (leukaemias, lymphomas, solid tumours) and neurodegenerative disorders such as Alzheimer's disease. In the framework of these diseases, research is devoted to various dysfunctional genes whose chromosomal location is established. The participants are continuing to develop in vivo models to study uncontrolled proliferation and Alzheimer's disease and to explore the molecular mechanisms underlying them.

In cancer research, work will focus on intracellular and surface expression of normal and abnormal genes and of antigens exploitable in cancer immunotherapy. Efforts will also be made to develop efficient gene delivery into cells. All efforts converge towards a major goal: to develop gene therapy schemes, whose targets par excellence are constitutional disorders, malignant proliferations, and possibly also neurodegenerative disorders.

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