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Role of HIF1A gene in the modulating of Ollier disease and Maffucci Syndrome

Grant number: 22/06590-3
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): September 30, 2022
Effective date (End): September 29, 2023
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:João Bosco Pesquero
Grantee:Patrícia Varela Calais
Supervisor: Nara Lygia de Macena Sobreira
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Johns Hopkins University (JHU), United States  
Associated to the scholarship:18/23367-0 - Study of the pathophysiological mechanisms of psychiatric disorders in Fabry's disease, BP.PD


Enchondromas are benign cartilaginous tumors that arise from the medulla of bones, typically in the metaphysis. They can arise as solitary or as multiple lesions, such as in the context of Ollier disease (OD) or Maffucci syndrome (MS). Somatic mutations in IDH1 and IDH2 have been identified in the enchondromas, chondrosarcomas, and vascular anomalies of ~80% of the individuals with OD and MS but not in unaffected tissue such as blood, muscle or saliva. The presence of IDH1 and IDH2 somatic variants in tumors of patients with OD and MS supports a role for disruption of the Hypoxia-inducible factor 1 pathway (HIF-1) as causative of OD and MS. HIF-1 is a basic helix-loop-helix-PAS domain transcription factor that under hypoxic conditions regulates the transcription of hundreds of genes in a cell type-specific manner. However, whether the HIF-1 pathway is upregulated or downregulated in these patients' enchondromas remains unknown, therefore, our goal is to define the effect of OD or MS causative variants in HIF-1 transcriptional activity. Our hypothesis is that causative variants of OD and MS cause downregulation of HIF1A and HIF1A-related genes. To confirm our hypothesis, we will use human mesenchymal stem cells (hMSC) and Induced Pluripotent Stem Cells (iPSCs) to produce knock-in cell-based to investigate the effect of causative variants identified in HIF1A, as well as identify differentially expressed genes and disrupted pathways in patients with OD and MS using RNAseq of enchondroma samples. (AU)

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