Pediatric Endocrinology Research

The clinical scientific studies in the field of pediatric endocrinology and diabetology focus on growth hormones, thyroid disease and diabetes (Prof. Urs Zumsteg and Gabor Szinnai, MD, PhD). Basic research projects are investigating molecular mechanisms of congenital hypothyroidism and thyroid development.

Congenital hypothyroidism is a state of insufficient thyroid hormonesupply to the organism, especially the brain, starting in utero. It represents the most frequent congenital endocrinopathy and themost frequent preventable cause of mental retardation. In 85% ofaffected patients, congenital hypothyroidism is caused by thyroiddysgenesis, a spectrum of defects of thyroid organogenesis and differentiation. However, only a minority of thyroid dysgenesis cases can be explained by monogenetic defects in thyroid specificgenes, suggesting alternative mechanisms.

In developing tissues, reversible histone acetylation represents a major epigenetic mechanism regulating gene expression. Acetylation of core histones is regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs) in a reciprocal way. The aim of this basic research project is to characterize the role of histone deacetylase activity for normal thyroid differentiation, and to investigate the effect of disturbed histone acetylation on development and function of thyrocytes in an ex vivo culture model of the embryonic thyroid.

In 2014, important results were obtained. First, we established afluorescence-activated cell sorting (FACS) protocol to discriminate 7 different cell populations, and to quantify cell type specific growth dynamics and epigenetic changes in embryonic and adult mousethyroids. This new tool is also applicable for detailed analyses of mouse models for thyroid cancer and autoimmunity. Second, using the new FACS protocol, our data clearly suggested a critical role of histone deacetylase activity for proper differentiation andproliferation of thyrocyte precursors and for normal angiogenesis within the developing thyroid gland. Disturbed acetylation in the developing thyroid resulted in disordered structural and functional differentiation, suggesting a new molecular mechanism for thyroiddys genesis in the human.

The clinical relevance of our results will be studied in cohortsof patients with congenital hypothyroidism analyzed by next generation sequencing techniques in the context of an international consortium.