The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells
Introduction: Down Syndrome (DS), caused by full or partial trisomy of chromosome 21 (T21 or pT21) presents with accelerated ageing, intellectual disability (ID) and Alzheimer’s disease (AD). The contributions of individual HSA21 gene overdoses to these features remain poorly understood. Methods: iP...
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| Médium: | Thesis-Doctor of Philosophy |
| Jazyk: | English |
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Nanyang Technological University
2021
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| On-line přístup: | https://hdl.handle.net/10356/153265 |
| _version_ | 1826123118315307008 |
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| author | Gough, Gillian |
| author2 | Foo Jia Nee |
| author_facet | Foo Jia Nee Gough, Gillian |
| author_sort | Gough, Gillian |
| collection | NTU |
| description | Introduction: Down Syndrome (DS), caused by full or partial trisomy of chromosome 21 (T21 or pT21) presents with accelerated ageing, intellectual disability (ID) and Alzheimer’s disease (AD). The contributions of individual HSA21 gene overdoses to these features remain poorly understood. Methods: iPSCs were generated from two individuals with pT21 and were utilised in combination with an already published isogenic model of DS . Isogenic iPSCs were generated by CRISPR/Cas9 genome modification of candidate HSA21 genes (APP, BACE2, DYRK1A and SOD1) or stable integration of fluorescent bio-sensors. Results: (i)We generated the first human isogenic model of the partial trisomy of the DS critical region (DSCR). (ii)The T21-caused cellular phenotypes of increased accumulation of mitochondrial H2O2, and DNA double-strand break repair foci, are visible in undifferentiated pluripotent hiPSCs; (iii)BACE2 is a dose-dependent repressor of AD-like pathology in cerebral organoids. |
| first_indexed | 2024-10-01T05:59:25Z |
| format | Thesis-Doctor of Philosophy |
| id | ntu-10356/153265 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:59:25Z |
| publishDate | 2021 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/1532652023-03-05T17:09:38Z The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells Gough, Gillian Foo Jia Nee Lee Kong Chian School of Medicine (LKCMedicine) Nizetic jianee.foo@ntu.edu.sg, d.nizetic@qmul.ac.uk Science::Medicine Introduction: Down Syndrome (DS), caused by full or partial trisomy of chromosome 21 (T21 or pT21) presents with accelerated ageing, intellectual disability (ID) and Alzheimer’s disease (AD). The contributions of individual HSA21 gene overdoses to these features remain poorly understood. Methods: iPSCs were generated from two individuals with pT21 and were utilised in combination with an already published isogenic model of DS . Isogenic iPSCs were generated by CRISPR/Cas9 genome modification of candidate HSA21 genes (APP, BACE2, DYRK1A and SOD1) or stable integration of fluorescent bio-sensors. Results: (i)We generated the first human isogenic model of the partial trisomy of the DS critical region (DSCR). (ii)The T21-caused cellular phenotypes of increased accumulation of mitochondrial H2O2, and DNA double-strand break repair foci, are visible in undifferentiated pluripotent hiPSCs; (iii)BACE2 is a dose-dependent repressor of AD-like pathology in cerebral organoids. Doctor of Philosophy 2021-11-15T07:31:49Z 2021-11-15T07:31:49Z 2021 Thesis-Doctor of Philosophy Gough, G. (2021). The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/153265 https://hdl.handle.net/10356/153265 10.32657/10356/153265 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University |
| spellingShingle | Science::Medicine Gough, Gillian The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title | The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title_full | The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title_fullStr | The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title_full_unstemmed | The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title_short | The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| title_sort | genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells |
| topic | Science::Medicine |
| url | https://hdl.handle.net/10356/153265 |
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