RESUMEN
OBJECTIVE: Approximately 6% of newborns at term are small for gestational age (SGA) and present a birth weight and/or length less than -2SD from the mean. SGA infants are at increased risk for perinatal morbidity, associated psychological and/or mental problems, persistent short stature (about 15% of subjects) and metabolic alterations. Insulin-like growth factors (IGFs), their common receptor (IGF1R) and their binding proteins (IGFBPs) play a critical role in fetal and postnatal growth. In these genes common polymorphisms, such as single nucleotide polymorphisms and variable number of tandem repeats, have been investigated with conflicting results with respect to SGA-related outcomes, and the functional role of these gene variants remains to be elucidated. DESIGN: The study group consisted of 100 pre-pubertal short children born SGA and 94 healthy controls, matched for sex and age, recruited at the Department of Biomedicine of Development Age of the Bari University and at the Paediatric Department of the Messina Hospital. In the present study we analyzed the allelic frequency of the polymorphisms -795 G/A, -667 G/A, -396 C/T in the IGFBP3 in SGA children and their influence on the basal and insulin-stimulated transcriptional activity of the gene. RESULTS: We found that the polymorphisms -667 G/A and -396 C/T in the IGFBP3 promoter region are capable of having an effect on the transcriptional activity of the gene, although with opposing effects. Interestingly, the -667 G/A polymorphism has a negative impact on the IGFBP3 transcription, while the -396 C/T polymorphism determines an increase of the transcriptional activity of the IGFBP3 gene promoter. Interestingly, we found that the -396 C/T polymorphism correlates with lower birth length in SGA children. Most importantly, while the diminished IGFBP3 transcriptional activity induced by the -667A polymorphism was significantly recovered after insulin administration (p-value<0.05), the increased transcriptional activity caused by the -396T polymorphism was not restored to baseline levels by insulin. CONCLUSIONS: Altogether our results demonstrated that the -667 G/A and the -396 C/T polymorphisms in IGFBP3 promoter region influence the basal transcriptional activity of the gene.
Asunto(s)
Regulación de la Expresión Génica , Recién Nacido de Bajo Peso/metabolismo , Recién Nacido Pequeño para la Edad Gestacional/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Polimorfismo de Nucleótido Simple/genética , Peso al Nacer/genética , Estatura/genética , Estudios de Casos y Controles , Niño , Preescolar , ADN/genética , Femenino , Frecuencia de los Genes , Edad Gestacional , Células HCT116 , Humanos , Hipoglucemiantes/uso terapéutico , Lactante , Recién Nacido , Insulina/uso terapéutico , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Italia , Luciferasas/metabolismo , Masculino , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genéticaRESUMEN
In recent years, new technologies have become available for imaging small animals. The use of animal models in basic and preclinical sciences, for example, offers the possibility of testing diagnostic markers and drugs, which is becoming crucial in the success and timeliness of research and is allowing a more efficient approach in defining study objectives and providing many advantages for both clinical research and the pharmaceutical industry. The use of these instruments offers data that are more predictive of the distribution and efficacy of a compound. The mouse, in particular, has become a key animal model system for studying human disease. It offers the possibility of manipulating its genome and producing accurate models for many human disorders, thus resulting in significant progress in understanding pathologenic mechanisms. In neurobiology, the possibility of simulating neurodegenerative diseases has enabled the development and validation of new treatment strategies based on gene therapy or cell grafting. Noninvasive imaging in small living animal models has gained increasing importance in preclinical research, itself becoming an independent specialty. The aim of this article is to review the characteristics of these systems and illustrate their main applications.