Selected notable advances:
- Diagnosis, molecular defect identification and targeted therapies of children and adults with many monogenic rare genetic, developmental, metabolic, endocrine, neurologic, immune and neoplastic disorders.
- Discovery of many novel mutations in the above disorders.
- Discovery of the influence of the circadian clock on the sensitivity of tissues to glucocorticoids.
- Discovery of a major long ncRNA (Gas5) as a major determinant of tissue glucocorticoid sensitivity of tissues in starvation states.
- Discovery of metabolic syndrome features in children conceived by in vitro fertilization (IVF), classic IVF vs.ICSI.
- Plasma metabolomic and proteomic studies in the above children revealed chronic insulin resistance and smolderin systemic inflammation.
- Discovery of a retro-transposon (HERV K10) in pre-implantation blastocysts and concurrent demethylation and activation of the DLK1-MEG3 gene.
- Advances in understanding the pathophysiology and in implementing novel therapies in Thalassemia.
- Advances in the understanding of the pathophysiology and therapy of children with cancer, including allogeneic bone marrow transplantation complications.
- Discovery of novel mutations in children with primary immunodeficiencies.
- Discovery of osteosarcopenia an extremely common condition, chronic systemic inflammation and hypercortisolism with a circadian rhythm abolishment or reversal in a large cohort of lean, overweight and obese males and females, starting in childhood (BIG DATA).
- Advances in understanding the pathophysiology of childhood infections and clinical trials of novel antibiotics.
U.R.I. is a unique national center for the clinical and molecular study and targeted therapies of genetic developmental, metabolic, endocrine, neurological, behavioral and neoplastic diseases of childhood and adolescence, including those of many Rare Diseases.
We live in an era that is characterized by a tremendously rapid expansion and accumulation of new knowledge, to a great extent due to an unparalleled advance in technology. Thus, we know that humans and their societies and civilizations are of unique complexity in the known cosmos. Humans have a complex genome that consists of about 3 billion bases, 20 thousand protein-coding genes,22 thousand ncRNA-coding genes, and 16 thousand pseudogenes, over 25 millions of single nucleotide polymorphisms or variants (SNPs or SNVs, indels), over 5000 copy number variants (CNVs ) containing many millions of bases, and over 20 million microsatellites. Human cells contain about 200 thousand transcripts (mRNA, ncRNA), and 200-260 thousand proteins. We have identified over 10 k disease-related mutations, most of them in the protein-coding areas of genes, while there are many more to be identified in the non-protein coding areas of genes, dispersed in the formerly called “junk DNA”.
On top of this immense genomic complexity, we have to add the so-called epigenetic complexity, which is many orders of magnitude greater. Regulatory changes in the activity of genes without alterations on the sequence of the DNA, primarily as a result of chemical modifications of the DNA bases, such as methylations, or in the neighboring chromatin, such as acetylations, are extremely important in developmental processes, such as embryonic and fetal tissue differentiation and morphogenesis, somatic tissue differentiation and regeneration, immune cell function, brain function and others. About 60% of human gene promoters have CpG islands, regions of DNA that can be methylated or demethylated and, hence, influence gene regulation. We expect that many trait- or disease-related “epimutations” will be discovered in the coming years.
The pinnacle of tissue complexity is in the human brain. It contains ~ 100 billion neurons (100×1012) x >10.000 synapses per neuron = >1018 synapses), ~ 100.000 km of fibers and ~ 1 trillion or more of glial cells. On top of this the brain is characterized by the process of plasticity, i.e. the ability to adaptively change function. The complexity of the human organism and his/her ecosystem has dictated the new qualifying terms of Systems Biology and Systems Medicine. The latest in biomedical terminology reflects these transformational changes and has defined modern contemporary Medicine as “Narrative and Precision Medicine”, Stratified Medicine, 4P Medicine (Personalized, Predictive, Preventive,Participatory). Pediatric Narrative and Precision Medicine has exactly the same meaning.
The above unraveling of the complexity of the human organism has been assisted by findings from patients with mono-,oligo-, or multi-genic changes that lead to physiologic variations or disease states. Medicine, and especially Pediatrics, have benefitted from the deciphering of human biologic complexity, as it regards our understanding of the pathophysiology, molecular or cellular diagnosis and from the rational studies of devising novel target therapies, tailored to the correction of the defects of the disorder.
Personalized Genomics Facility
Services and support in high-throughput, genome wide research, including genomic applications (whole genome sequencing, exome sequencing, whole genome mapping, genotyping, etc), transcriptomic (RNA-Seq, smallRNA-Seq), epigenomic (MeDIP-Seq, ChIP-Seq, bisulfide sequencing, etc.), metagenomic (microbial ecology), genotyping services.Next Generation Sequencer
Dyslipidemia is one of the predisposing factors for the onset of metabolic syndrome and atherosclerosis, contributing to increased cardiovascular risk. For this reason, the pursuit and analysis of pathological lipid profile from childhood is crucial.
One of the most common forms of dyslipidemias is Familial Hypercholesterolemia (FH) with an asymptomatic heterozygous picture. It is estimated that in Greece the number of patients with FH is more than 40,000, with the majority of them remaining undiagnosed.
The Dyslipidemia Unit provides the molecular diagnosis of FH and other dyslipidemias in adults and children and, according to the doctors’ clinical indications, performs genetic testing to confirm the presence or absence of eclipse.
Data Analysis, Integration, Modeling Unit
The Unit will provide bioinformatic and data analysis resources for individual medical genomic applications.Also, analysis of genetic variability, transcriptome profiling, pharmacogenomic analyses, individual epigenetic profiling, modeling, efficient reference genome indexing ExomeSeq data analysis.
PET Imaging Unit
Identifying imaging biomarkers, visualizing molecular processes for early diagnosis. Identifying pathophysiologic alterations when disease is present. Allowing diagnostic precision as well as treatment monitoring and response.Combining targeted imaging and therapy (theragnostics) and Individualizing, image-guided therapeutic interventions.
Proteomics and Metabolomics Unit
Improved sample separation and sensitivity, isolation of exosomes, accurate quantification in parallel with identification High-throughput analysis of proteins and metabolites, including neurotransmitters, lipids and steroids. Metabolic profiling and fingerprinting.LC/MS apparatus, needed also in the existing Bioanalytical Unit of the Choremeion Research Laboratory. The existing system is barely functioning.
Advanced Imaging Facility
Discovery and validation of novel biomarkers suitable for patient stratification and disease prognosis.These include:light sheet and multi-photon microscopy systemprobe-based in vivo imaging for assessing novel biomarkers for disease progression
Clinical Tissue Sampling Facility
Strategies implementing best practices for collecting, cataloguing, and storing samples and specimens (fresh, frozen or FFPE samples) for use in the above advanced technology platforms.Continuation of on-going and creation of new sample libraries. Exosome production and isolation, needed also in the Proteomics and Metabolomics Facility.Expanded sample storage facility with existing and novel sample libraries
Cellular Therapies Facility
Strategies implementing best practices for cellular immunotherapies, such as CAR-T.Preparing immunosensitized T cells for transplantation in children with cancer, mainly acute lymphocytic leukemia. Implementations of the CRISPR-cas9 methods to modify the genetics of cells.Expansion of our GMP facility for manufacturing our cellular medical therapy products; Bioreactor, to also be used by our Proteomics and Metabolomics Facility.Opera or Operetta (High Throughput, High Resolution Cell Screening System, based on Confocal Technology).Expansion of our GMP facility for manufacturing our cellular medical therapy products; Bioreactor, to also be used by our Proteomics and Metabolomics Facility.