454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction
OBJECTIVES/GOALS: We will use control- and DMD-engineered heart tissues to better model and investigate DMD cardiomyopathy. We will primarily assess cardiac calcium handling, mitochondrial function, and mitochondrial calcium handling, as calcium regulation and mitochondrial function are known to be...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2023-04-01
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| Series: | Journal of Clinical and Translational Science |
| Online Access: | https://www.cambridge.org/core/product/identifier/S205986612300479X/type/journal_article |
| _version_ | 1797840400354902016 |
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| author | Patrick Ernst Michaela Dora Lufang Zhou Brenda Ogle Forum Kamdar |
| author_facet | Patrick Ernst Michaela Dora Lufang Zhou Brenda Ogle Forum Kamdar |
| author_sort | Patrick Ernst |
| collection | DOAJ |
| description | OBJECTIVES/GOALS: We will use control- and DMD-engineered heart tissues to better model and investigate DMD cardiomyopathy. We will primarily assess cardiac calcium handling, mitochondrial function, and mitochondrial calcium handling, as calcium regulation and mitochondrial function are known to be affected in DMD. METHODS/STUDY POPULATION: We will use patient-derived stem cells, differentiated into cardiomyocytes in bioprinted 3D heart tissue muscle chambers to better model DMD cardiomyopathy. We will look at calcium handling and general mitochondrial function, as well as mitochondrial calcium handling, using a novel multifunctional genetic probe I previously developed allowing for simultaneous observation of cytosolic and mitochondrial calcium in real time. Optical mapping will also be used for tissue-level analysis. We will establish the functional differences at baseline, and then progress heart failure in the tissues to see how the abnormalities seen in the DMD tissues may get worse. Finally, we will investigate the effects of early restoration of dystrophin function on the effects of DMD cardiomyopathy development. RESULTS/ANTICIPATED RESULTS: We anticipate that DMD tissues will show more irregular/abnormal calcium handling, as seen in 2D hiPSC-CMs, as well as disruptions to mitochondrial function and ultrastructural development, as well as a decreased synchronization between cytosolic and mitochondrial calcium dynamics. We anticipate that these abnormalities will be exacerbated as the disease state progresses, but at least partially ameliorated with the restoration of dystrophin function. DISCUSSION/SIGNIFICANCE: DMD is a fatal disease with no known cure. Patients develop heart failure in their teens and die in their 20s, so any new insight that may prolong life and improve quality of life for patients is drastically needed. This would be the most accurate preclinical model of DMD cardiomyopathy to date and would investigate yet-untapped aspects of the disease state. |
| first_indexed | 2024-04-09T16:14:29Z |
| format | Article |
| id | doaj.art-4ba9e75865e24a3199530e578e9adbdb |
| institution | Directory Open Access Journal |
| issn | 2059-8661 |
| language | English |
| last_indexed | 2024-04-09T16:14:29Z |
| publishDate | 2023-04-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj.art-4ba9e75865e24a3199530e578e9adbdb2023-04-24T05:55:57ZengCambridge University PressJournal of Clinical and Translational Science2059-86612023-04-01713413510.1017/cts.2023.479454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial DysfunctionPatrick Ernst0Michaela Dora1Lufang Zhou2Brenda Ogle3Forum Kamdar4University of MinnesotaUniversity of MinnesotaThe Ohio State UniversityUniversity of MinnesotaUniversity of MinnesotaOBJECTIVES/GOALS: We will use control- and DMD-engineered heart tissues to better model and investigate DMD cardiomyopathy. We will primarily assess cardiac calcium handling, mitochondrial function, and mitochondrial calcium handling, as calcium regulation and mitochondrial function are known to be affected in DMD. METHODS/STUDY POPULATION: We will use patient-derived stem cells, differentiated into cardiomyocytes in bioprinted 3D heart tissue muscle chambers to better model DMD cardiomyopathy. We will look at calcium handling and general mitochondrial function, as well as mitochondrial calcium handling, using a novel multifunctional genetic probe I previously developed allowing for simultaneous observation of cytosolic and mitochondrial calcium in real time. Optical mapping will also be used for tissue-level analysis. We will establish the functional differences at baseline, and then progress heart failure in the tissues to see how the abnormalities seen in the DMD tissues may get worse. Finally, we will investigate the effects of early restoration of dystrophin function on the effects of DMD cardiomyopathy development. RESULTS/ANTICIPATED RESULTS: We anticipate that DMD tissues will show more irregular/abnormal calcium handling, as seen in 2D hiPSC-CMs, as well as disruptions to mitochondrial function and ultrastructural development, as well as a decreased synchronization between cytosolic and mitochondrial calcium dynamics. We anticipate that these abnormalities will be exacerbated as the disease state progresses, but at least partially ameliorated with the restoration of dystrophin function. DISCUSSION/SIGNIFICANCE: DMD is a fatal disease with no known cure. Patients develop heart failure in their teens and die in their 20s, so any new insight that may prolong life and improve quality of life for patients is drastically needed. This would be the most accurate preclinical model of DMD cardiomyopathy to date and would investigate yet-untapped aspects of the disease state.https://www.cambridge.org/core/product/identifier/S205986612300479X/type/journal_article |
| spellingShingle | Patrick Ernst Michaela Dora Lufang Zhou Brenda Ogle Forum Kamdar 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction Journal of Clinical and Translational Science |
| title | 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction |
| title_full | 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction |
| title_fullStr | 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction |
| title_full_unstemmed | 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction |
| title_short | 454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction |
| title_sort | 454 a human 3d model of duchenne muscular dystrophy cardiomyopathy to investigate calcium regulation and mitochondrial dysfunction |
| url | https://www.cambridge.org/core/product/identifier/S205986612300479X/type/journal_article |
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