Role of ret and modifier genes in human disease

Información del proyecto

Identificador del acuerdo de subvención: BMH4972107

Proyecto cerrado

Fecha de inicio 1 Junio 1997

Fecha de finalización 30 Noviembre 2000

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

€ 600 096,00

Coordinado por

Université Paris Val-de-Marne
France

Objetivo

- To map modifiers of Hirschsprung disease (HSCR) and papillary thyroid carcinomas (PTC) in mice and in humans.
- To construct new ret knock-outs.
- To further develop a mouse neural crest culture system.
- To identify the biological and biochemical effects of HSCR RET mutations in an in vitro expression system which will be integrated by the use of a panel of recombinant molecules known to be involved in receptor tyrosine kinase (RTK) triggered pathways.
- To identify possible interactions between the RET pathway and that mediated by the endothelin receptor B (EDNRB).
- To establish the developmental potentials of enteoic nervous system (ENS) progenitors and rescue of the aganglionic gut phenotype of ret knock-out homozygous embryos by introducing into the embryo ret+ positive progenitors.

The RET proto-oncogene is at the origin of one of the most interesting models of human disease caused by mutations in a receptor tyrosine kinase gene. RET mutations or heterozygous deletions of the whole gene cause the autosomal dominant form of congenital megacolon or Hirschsprung disease (HSCR), a relatively frequent genetic malformation of the enteric nervous system. Somaticre arrangements of RET are involved in the aetiology of a variable proportion of papillary thyroid carcinomas (PTC), the most common type of thyroid tumour whose prevalence is increasing in areas heavily exposed to radioactive fallout after the Chernobyl accident in 1986. Moreover, germline RET mutations are associated with the three variants of the rare inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2A, MEN2B) and Familial Medullary Thyroid Cancer or FMTC. These different effects of RET mutations have been correlated with loss of function or gain of function mechanisms using in vitro expression systems and transgenic or knock-out mouse models. In some human pedigrees the recurrence of both phenotypes (colon aganglionosis and thyroid cancer) is apparently associated with only a single RET mutation. The question then arises whether this observation can be explained in terms of interacting or modifier genes which could influence the expression of RET. The existence and role of modifiers of the HSCR and thyroid cancer phenotypes remain at present unknown and a large part of this grant application describes ideas and experiments which might offer new leads in this field of research.

The background knowledge of the project originated mainly from European laboratories and in a significant proportion from partner laboratories involved in this proposal, which aims at continuing the tradition of European leadership in the field. The novel approach in the field of RET research is the attempt to map and study genes others than RET which modify the HSCR or the PTC phenotype.

The experimental systems available in partner laboratories make it possible to envisage that the following objectives will be attained:
1. mapping of modifiers of HSCR and PTC in mice and in humans;
2. construction of new ret knock-outs;
3. further development of a mouse neural crest culture system;
4. identification of the biological and biochemical effects of HSCR RET mutatio in an in vitro expression system which will be integrated by the use of a panel of recombinant molecules known to be involved in RTK triggered pathway;
5. identification of possible interactions between the RET pathway and that mediated by the endothelin receptor B (EDNRB);
6. establishment of the developmental potentials of ENS progenitors and rescue the aganglionic gut phenotype of ret knock-out homozygous embryos by introducing into the embryo ret+ positive progenitors.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › neurobiología
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › medicina clínica › oncología
• ciencias médicas y de la salud › medicina clínica › embriología

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 5.2 - Analysis of gene function and interaction

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

Université Paris Val-de-Marne

• Aportación de la UE: Sin datos
• Dirección: 51,Avenue du Mal. de Lattre de Tassigny ; 94010 Créteil ; Francia
• Coste total: Sin datos

Participantes (5)

FINNISH CANCER REGISTRY

Finlandia

• Aportación de la UE: Sin datos
• Dirección: 21B,LIISANKATU 21B ; 00170 HELSINKI
• Coste total: Sin datos

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

Francia

• Aportación de la UE: Sin datos
• Dirección: 150,Cours Albert-Thomas 150 ; 69372 LYON
• Coste total: Sin datos

ISTITUTO GIANNINA GASLINI

Italia

• Aportación de la UE: Sin datos
• Dirección: Largo Gerolamo Gaslini 5 ; 16148 GENOVA
• Coste total: Sin datos

Institut National de la Santé et de la Recherche Médicale

Francia

• Aportación de la UE: Sin datos
• Dirección: Chemin de Vallombrose ; 06107 Nice
• Coste total: Sin datos

MRC National Institute for Medical Research

Reino Unido

• Aportación de la UE: Sin datos
• Dirección: The Ridgeway Mill Hill ; NW7 1AA London
• Coste total: Sin datos