Abstract P457: Systems Analysis To Understand The Impact Of The CDK Module On Cardiomyocyte Proliferation

• DOI: 10.1161/res.129.suppl_1.p457
• Publication Date: 2021-11-22T12:35:29Z
• Authors: Bryana N Harris; Laura Woo; Jeffrey J Saucerman
• Keywords: Cyclin A; E2F

Rationale: Heart failure is caused by the inability of adult mammalian hearts to overcome loss cardiomyocytes (CMs). This due partly limited proliferative capacity CMs, which exit cell cycle and do not undergo division. Current knowledge in cardiac regeneration lacks an understanding molecular regulatory networks that determine whether CMs will progress through proliferate. Our goal use computational modeling understand expression activation levels core network, specifically cyclins cyclin-cyclin-dependent kinase (CDK) complexes. Methods: A model dynamics was curated using previously published studies CM proliferation regulators. incorporates those regulators known stimulate G1/S G2/M transitions CDKs. The activity each 22 network nodes (22 reactions) predicted a logic-based differential equation approach. CDK then coupled with minimal ODE phase distributions validated based on descriptions experimental data from literature. To prioritize key for validation, we performed sensitivity analysis stimulating individual knockdown every node measuring fractional all nodes. Results: confirmed p21 Rb protein overexpression E2F transcription factor cyclinD-cdk4 showed increase cells going DNA synthesis entering mitosis. combined p27 Cyclin D-cdk4 decrease expression, respectively. Of 14 predictions, 12 agreed comprehensive suggests (a driving synthesis) positively regulated cyclin D while negatively GSK3B, SMAD3, pRB. Conclusion: enables us predict how respond stimuli identify potential therapeutic induce cardiomyocyte proliferation.