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Investigation of osteogenesis, chondrogenesis, and phenotype rescue in Treacher Collins syndrome using 3D culture models

Grant number: 22/14419-2
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): March 01, 2023
Effective date (End): December 31, 2023
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Maria Rita dos Santos e Passos Bueno
Grantee:Gabriella Shih Ping Hsia
Supervisor: Warren Grayson
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Johns Hopkins University (JHU), United States  
Associated to the scholarship:18/21706-2 - Treacher Collins Syndrome: mechanisms responsible for clinical variability and in search of molecules to rescue the phenotype, BP.DD


Craniofacial malformations comprise nearly one-third of all congenital birth defects and generally arise from disturbances of neural crest cells (NCCs) during the embryonic development. Treacher Collins syndrome (TCS) is a rare congenital disorder, mainly characterized by craniofacial malformations. There is no efficient treatment for TCS, especially for severely affected patients. Most of the cases (~93%) are caused by pathogenic mutations in TCOF1, causing the impairment of ribosome biogenesis and/or rDNA damage repair. These impairments associated with oxidative stress due to high levels of reactive oxygen species, leads to apoptosis at the neural plate border, compromising NCCs migration, resulting in craniofacial malformations. These mechanisms that occur during TCS early embryogenesis are well established, but little is known about later stages of TCS embryo's development, such as in bone and cartilage formation. Since redox state maintenance and ribosome biogenesis are essential for osteogenesis and chondrogenesis, it is important to investigate these processes in TCS. Our preliminary data in 2D cell culture indicates that osteogenesis and chondrogenesis in TCS are also impaired, but a further evaluation is necessary. Therefore, we propose here to study TCS osteogenesis and chondrogenesis using 3D culture models, as they reproduce in vivo biology with greater fidelity than 2D cell cultures. This 3D TCS model will also enable phenotype rescue assays. Understanding these processes in this TCS model, and evaluating different molecules in phenotype rescue assays, will contribute for the development of better treatments for TCS patients that may be applied during their reconstructive surgeries and help with their bone and cartilage regeneration. (AU)

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