The "Genetics and Control of Diabetes and other Endocrine Disorders" Research Group is a clinical and basic research group with a wide translational activity. At national level, this group belongs to the CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) and to the CIBER of Rare Diseases (CIBERER) of the ISCIII. At international level, the group takes part in several research networks, such as European Type 1 Diabetes Genetic Network (ET1DGN) and the Hvidore Study Group for Childhood Diabetes.
The scientific activities include the study of the genetic mechanisms which are involved in the development of endocrine and metabolic diseases (diabetes) as well as in their prevention and the search of novel therapeutic strategies (immunomodulation and/or cellular therapy) towards the improvement in disease control. In this regard, genetic determinants of susceptibility to autoimmune diabetes and early diagnostic immunological biomarkers are investigated. Moreover, with regard to disease prevention, the group participates in several international clinical trials aimed to the immune tolerance induction with autoantigens against type 1 diabetes, such as the TRIGR Study (Trial to prevent IDDM in genetically at risk children) or the Diamyd Study (anti-GAD). With regard to novel therapeutic strategies, the group's scientific activity focuses on the analysis of several aspects of cellular therapy which is based on islets transplant and differentiation of pancreatic beta-cells. Moreover, the group is also involved on the research of molecular modifications in phospho-calcium metabolism disorders and other rare endocrine diseases.
Research on peptide metabolism in human sperm samples, particularly in sperm cells, under physiological and/or pathological conditions is also carried out.
Hirschsprung disease (HSCR), a hereditary disease, is characterized by the lack of neurons in the digestive system, which blocks the intestinal motility resulting in a functional obstruction. The estimated incidence of the disease is approximately 1 in 5000 live births, approximately four times more common in male than in female. Current treatment of the disease is surgery to bypass the part of the colon that has no nerve cells and to join the healthy areas. Although this treatment is effective, it has a profound effect on the patient's quality of life. Over the last decades, the development of novel surgical techniques have decreased patients' mortality and morbidity, which has allowed the genetic analysis of this pathology, both at patients' and relatives' level.
The disease is considered to be a neurocristopathy, which may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest cell lineage. The defect usually takes place between the 5th and 12th week of gestation, during the generation of the enteric nervous system (ENS). Children may display symptoms during the first two months of life, although in some cases the diagnosis is done through childhood or even later as adults. If surgery is not performed on time, HSCR's patient can develop further complications such as enterocolitis and/or potential intestinal perforation.
RET (REarranged during Transfection) proto-oncogene is expressed in the enteric neuronal progenitors during the colonization of the intestinal tract in the embryonic development. This gene belongs to the family of cadherins and encodes a receptor tyrosine kinase. These receptors are localized in the cellular surface and transduce the signals involved in growth and cellular differentiation. Mutations and polymorphisms in the gene sequence may alter both its expression and function, and may be associated to Hirschsprung disease. Moreover, there are other mutations which are associated with the development of several types of endocrine diseases, including medullary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). The presence of SNP may determine the progression of the disease, and their different combinations (haplotypes) may increase genetic predisposition to suffer HSCR disease. For this reason, genetic analysis is crucial in to stablish a hereditary pattern and to identify the genetic modifications in the RET gene.
Currently, the therapeutic strategies for enteric neurocristopathy are surgery and parenteral nutrition. The available data show that design of novel therapies for this pathology is crucial. Over the last decade, breakthroughs in Molecular Biology and Genetics have significantly increased our knowledge in the development and function of the enteric nervous system. These techniques, in combination with advances in Pharmacology and Stem cell Biology, have allowed the identification of novel tools and therapeutic targets. These strategies may be used to replace defective areas of the enteric nervous system, help the recovery of the damage tissue, and thus improve patient's quality of life.
Main lines of research:
- Immunogenetics of type 1 diabetes and other autoimmune associated disorders
- Early diagnosis and biomarkers of type 1 diabetes
- Cellular therapy in diabetes
- Molecular modifications in the development and function of endocrine pancreas
- Genetic disorders in rare endocrine diseases
- Disorders in the phospho-calcium metabolism
- Sperm cells metabolism
- Ovary and hormonal activity
- Sexual glands and metabolic activity (future line of research)
- Phospho-calcium metabolism (future line of research)
- Genetic study in children with Hirschsprung disease and their relatives. Search of mutations and disease-associated polymorphisms in order to establish a genetic model
- Analysis of RET proto-oncogene sequence in patients with gene-related diseases, such as Hirschsprung disease, occasional medullary thyroid cancer and multiple endocrine neoplasia type 2 (MEN2)
- Novel mechanisms involved in the progression of metabolic liver disease: from hepatic steatosis to hepatocellular carcinoma