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UID:DSC-21347
DTSTART;TZID=Europe/Berlin:20241025T110000
SEQUENCE:1729835162
TRANSP:OPAQUE
DTEND;TZID=Europe/Berlin:20241025T120000
URL:https://dresden-science-calendar.org/calendar/en/detail/21347
LOCATION:MPI-CBG\, Pfotenhauerstraße 10801307 Dresden
SUMMARY:Lilianty: Investigating collagen II cartilage disorders using hiPSC
 -derived cartilage organoids
CLASS:PUBLIC
DESCRIPTION:Speaker: Jinia Lilianty\nInstitute of Speaker: Murdoch Children
 ’s Research Institute\, The University of Melbourne\, Australia\nTopics:
 \n\n Location:\n  Name: MPI-CBG (MPI-CBG: Galleria)\n  Street: Pfotenhauer
 straße 108\n  City: 01307 Dresden\n  Phone: +49 351 210-0\n  Fax: +49 351
  210-2000\nDescription: Collagen II (COL2A1) is a crucial structural prote
 in in cartilage extracellular matrix. COL2A1 mutations lead to various car
 tilage disorders\, ranging from mild early-onset arthritis to lethal perin
 atal malformations. Existing in vitro disease models do not use disease-sp
 ecific cells and mouse models do not replicate human physiology\, making t
 he study of collagen II disorders particularly challenging. Consequently\,
  the molecular pathology of these mutations is not fully understood\, and 
 no effective drug therapies are available for patients. To tackle this pro
 blem\, we have modelled a severe and a lethal cartilage disorder caused by
  heterozygous COL2A1 p.R989C and p.G1113C mutations\, respectively. We int
 roduced the patient mutations into hiPSCs using CRISPR/Cas9 gene editing. 
 Mutant and isogenic control lines were differentiated into human cartilage
  organoids using our developed protocol\, then we used these organoids to 
 uncover molecular mechanisms of these mutations. While both mutations caus
 e similar collagen biosynthetic defects\, they are more severe in p.G1113C
  mutant organoids compared to p.R989C. The mutant organoids exhibited slow
  collagen II folding\, intracellular retention\, dilated endoplasmic retic
 ulum (ER)\, and reduced and abnormal collagen II fibrils in the extracellu
 lar matrix\, mirroring findings in patients and mouse models. Despite thes
 e similarities\, the mutations affected chondrocyte maturation differently
 : p.R989C accelerated hypertrophy\, whereas p.G1113C delayed it\, potentia
 lly explaining the observed bone defects in patients. Using unbiased whole
  transcriptomics analysis\, we found that both mutant collagen II proteins
  activate the PERK arm of the ER unfolded protein response (UPR)\, suggest
 ing ER stress\, consistent with the dilated ER found in the mutants. This 
 study expands our understanding of COL2A1 molecular mechanisms in clinical
 ly relevant human disease models. Our in vitro models\, which reproduce di
 sease phenotypes\, have significant potential for pre-clinical drug screen
 ing. Ultimately\, we can therapeutically target the pathogenic pathway ide
 ntified in this study\, potentially leading to new therapeutic strategies 
 for collagen II disorders.
DTSTAMP:20260409T075054Z
CREATED:20241010T054117Z
LAST-MODIFIED:20241025T054602Z
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