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Conference Paper: The integrated stress response in skeletal development and disease
Title | The integrated stress response in skeletal development and disease |
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Authors | |
Issue Date | 2018 |
Publisher | ComBio 2018. |
Citation | ComBio 2018, Sydney, Australia, 22-27 September 2018 How to Cite? |
Abstract | The integrated stress response (ISR) has a central role in maintaining homeostasis in cells experiencing many forms of cellular stress such as biomechanical loading, oxidative stress, hypoxia, endoplasmic
reticulum (ER) stress. Induction of the ISR is important for maintaining cells in normal development and is associated with diverse congenital and common diseases. Human congenital skeletal dysplasia caused
by disrupted development of the growth plate is often associated with mutations that trigger ER stress that induces the Unfolded Protein Response (UPR). Here, we exploited a mouse model of Metaphyseal
Chondrodysplasia type Schmid (MCDS) to provide mechanistic insight into the impact of the ISR on cell fate. We show that the ISR core protein kinase RNA-like ER kinase (PERK) signaling pathway that
modulates translation, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4 directed transactivation of Sox9. Treatment of mutant mice with a chemical inhibitor of PERK signaling
prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR may be a therapeutic strategy for stress-induced skeletal disorders. |
Description | Symposium 9: Developmental Genetics of Human Disease ComBio2018 incorporates the annual meetings of: Australian Society for Biochemistry and Molecular Biology, Australian Society of Plant Scientists, Australia and New Zealand Society for Cell and Developmental Biology, International Society of Differentiation, New Zealand Society of Plant Biologists & New Zealand Society for Biochemistry and Molecular Biology |
Persistent Identifier | http://hdl.handle.net/10722/271926 |
DC Field | Value | Language |
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dc.contributor.author | Cheah, KSE | - |
dc.date.accessioned | 2019-07-20T10:32:14Z | - |
dc.date.available | 2019-07-20T10:32:14Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | ComBio 2018, Sydney, Australia, 22-27 September 2018 | - |
dc.identifier.uri | http://hdl.handle.net/10722/271926 | - |
dc.description | Symposium 9: Developmental Genetics of Human Disease | - |
dc.description | ComBio2018 incorporates the annual meetings of: Australian Society for Biochemistry and Molecular Biology, Australian Society of Plant Scientists, Australia and New Zealand Society for Cell and Developmental Biology, International Society of Differentiation, New Zealand Society of Plant Biologists & New Zealand Society for Biochemistry and Molecular Biology | - |
dc.description.abstract | The integrated stress response (ISR) has a central role in maintaining homeostasis in cells experiencing many forms of cellular stress such as biomechanical loading, oxidative stress, hypoxia, endoplasmic reticulum (ER) stress. Induction of the ISR is important for maintaining cells in normal development and is associated with diverse congenital and common diseases. Human congenital skeletal dysplasia caused by disrupted development of the growth plate is often associated with mutations that trigger ER stress that induces the Unfolded Protein Response (UPR). Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide mechanistic insight into the impact of the ISR on cell fate. We show that the ISR core protein kinase RNA-like ER kinase (PERK) signaling pathway that modulates translation, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4 directed transactivation of Sox9. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR may be a therapeutic strategy for stress-induced skeletal disorders. | - |
dc.language | eng | - |
dc.publisher | ComBio 2018. | - |
dc.relation.ispartof | ComBio 2018 | - |
dc.title | The integrated stress response in skeletal development and disease | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Cheah, KSE: hrmbdkc@hku.hk | - |
dc.identifier.authority | Cheah, KSE=rp00342 | - |
dc.identifier.hkuros | 299157 | - |
dc.publisher.place | Australia | - |