Ph.D. Projects


All projects will be carried out in the Biocrystallography Unit of the DIBIT in a collaborative and highly stimulating environment.

Structure and function of AIRE, a transcription factor linked to autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)

The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the first systemic autoimmune disease caused by defects in a single gene. The defective gene was discovered in 1997, and termed AIRE for autoimmune regulator. The AIRE gene encodes for a multidomain nuclear protein, whose function is largely unknown. AIRE contains two PHD domains, a HSR/CARD domain, and a putative DNA-binding domain termed SAND. AIRE is predominantly expressed in thymic medullary epithelial cells where it promotes the expression of tissue specific antigens. The current hypothesis holds that mutations affecting AIRE activity may reduce the thymic expression of antigens that are crucial for the negative selection of T cells. Autoreactive T cells in turn reach the periphery, and mediate the onset of disease. The molecular and functional details of AIRE are largely unknown. Only the function of the first PHD domain has been elucidated, highlighting its role in binding the unmethylated histone H3, and hence strengthening the involvement of AIRE with the process of chromatin remodelling. Yet several questions remain unanswered on the overall architecture of AIRE, and the functional interplay between the different domains. In particular, it is yet unknown how missense mutations in the HSR/CARD domain affect the biological activity of AIRE. The project aims at a molecular, structural, and functional characterization of the AIRE protein, using a combination of techniques ranging from site-specific mutagenesis, to biophysical techniques such as NMR and X-ray crystallography, mass spectrometry, and studies in vitro. The overall goal is to establish the function of the different domains of AIRE, and assess the effect of the pathogenic mutations on the protein. These results will shed light on possible mechanisms that lead to the development of autoimmune disease. The successful candidate will receive state-of-the-art training in protein biochemistry, cell biology, and biophysics.