Your mission
HOST INSTITUTION:
▪ Ospedale San Raffaele SRL (OSR). Italy > Milan
▪ Ospedale San Raffaele SRL (OSR). Italy > Milan
About IMMERGE
In the realm of cutting-edge research and academic excellence, the IMMERGE MSCA Doctoral Network (DN) stands as an extraordinary training initiative, embracing a multidisciplinary perspective that spans various domains of knowledge. The program is dedicated to recruit 12 remarkable Doctoral Candidates (DCs) within the field of Immunology, Epigenetics, Omics and Gene Editing Technologies and Bioinformatics. The objective of the program is to answer several essential questions regarding the Inborn Errors of Immunity (IEI), such what is the relationship between genetic mutations and the wide clinical phenotypic expressivity and drug response in different individuals? How are the specific effects of these mutations modulated by the genetic background and/or environmental factors? What is the interplay between these mutations and a wealth of cell signalling pathways and transcriptional factors? Can we correct them? Inborn Errors of Immunity (IEI) represent a paradigm for (i) exploring the communication between genetics, epigenetic and environmental determinants and (ii) testing the potential of gene editing methods.
The DCs will be enrolled in top-notch academic and non-academic partners working with experts in immunology, genetics, epigenetics, proteomics, single cell omics, bioinformatics, and gene correction. Participating institutions represent 7 different countries, with 8 members in academia and 2 non-academic, from the biotech sector. In addition, the overall programme has designed a
tailored training programme in which 16 Associated Partners bring additional expertise to the
MSCA DN.
Individual research project
Doctoral Candidate 6: Dissecting the role of dysfunctional telomeres to stem cell biology and immunity
Rationale and Objectives: Dyskeratosis congenita (DC) is a genetic inherited syndrome characterised by short telomeres. Telomerase is a specialised ribonucleoprotein complex composed of Telomerase Reverse Transcriptase (TERT), Telomerase RNA Component (TERC), and dyskerin, which stabilises telomerase complex. More than half of DC patients harbour mutations in telomere maintenance genes and immunodeficiencies and bone marrow failure (BMF) represent their main cause of mortality. Telomere attrition is one of the best-characterised mechanisms of cellular senescence. We hypothesise that telomere shortening triggers a DDRdependent senescence in DC patients' BM-derived HSPC leading to severe BMF and proinflammatory detrimental programs. DC6 will focus on the autosomal forms of the disease caused by TERC gene mutations, preferentially affecting paediatric patients. To that end, DC-like human HSPC will be generated by the (CRISPR)-Cas system. Our engineered DC human model will allow us to study the causes of HSPC premature exhaustion and immune dysfunctions, with a specific focus on: 1) exacerbated DDR (imaging/flow cytometry); 2) transcriptional and epigenetic changes (scRNAseq/histone marks); 3) proinflammatory phenotype (luminex assay) and will be used as a platform for the development of new therapies for DC patients. Functional experiments will include colony-forming assays in semisolid medium and long-term hematopoietic reconstitution by transplantation. Validation experiments will be performed in
BM-derived HSPCs from DC patients obtained through a collaboration with the Gaslini Hospital in Genoa.
Host institution: Ospedale San Raffaele SRL
Degree awarding institution: Università Vita-Salute San Raffaele, Milan (Italy)
Supervisor: Dr. Raffaella Di Micco
Planned secondment(s): IJC to utilize epigenetics to identify the molecular determinants of HSPC dysfunctions, m13-15 (1 months); GRL (Vento-Tormo), to identify the impact of the genetic inactivation in cellular and molecular phenotype by sc-omics, m20-22 (2 months). Finally, the DC will do a secondment at OneChain to learn the standards of genetic manipulation in the biotech sector, m30-31 (1 month).