DOT1L Modulation for Cardiomyocyte Proliferation in Cardiac Repair
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Chemotherapeutic agents adversely affect the heart by targeting pathways crucial for heart function, and mammalian cardiomyocytes cannot regenerate due to cell cycle withdrawal, necessitating strategies to promote cardiomyocyte proliferation for cardiac regeneration.
Innovation Solution
Modulating DOT1L gene expression or function in mammalian cardiac cells using agents like chemical inhibitors, shRNA, or CRISPR gene editing to upregulate or downregulate DOT1L activity, thereby promoting cardiomyocyte proliferation and cardiac regeneration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapeutic agents are used to treat cancer, then cancer cell growth is controlled, but cardiomyocyte function and heart health deteriorate
Solution Approach 1:
The patent segments the biological pathways by targeting specific epigenetic enzymes (DOT1L, EZH2) that are crucial for cardiomyocyte cell cycle regulation, rather than using broad-spectrum chemotherapeutic agents. This allows selective intervention in cancer-related pathways while preserving heart function.
Solution Approach 2:
The patent uses epigenetic enzymes as intermediaries to bridge cancer treatment and heart protection. By modulating these enzymes' activity, the treatment can influence both cancer cell proliferation and cardiomyocyte function through a common molecular mechanism, reducing off-target effects.
2Stability of the object's composition
If cardiomyocytes are prevented from dividing to maintain heart function, then heart stability is maintained, but cardiac regeneration capability is lost
Solution Approach 1:
The patent introduces dynamic control of cardiomyocyte proliferation through epigenetic modulation. By using small molecule inhibitors that can be administered temporarily after injury, the system transitions from a static post-mitotic state to a dynamic proliferative state when needed, then returns to stability.
Solution Approach 2:
The patent changes the epigenetic parameters (histone methylation levels via DOT1L and EZH2 inhibition) to alter cardiomyocyte behavior. This parameter change allows cells to re-enter the cell cycle and proliferate without permanently altering their differentiated function, enabling regeneration while maintaining stability.
3Productivity
If DOT1L function is inhibited to promote cardiomyocyte proliferation, then cardiac regeneration is enhanced, but potential harmful effects on other biological pathways may occur
Solution Approach 1:
The patent applies partial inhibition of DOT1L function rather than complete blockade, using small molecule inhibitors at controlled doses and durations. This partial action is sufficient to promote cardiomyocyte proliferation for regeneration while minimizing disruption to other biological pathways that require DOT1L function.
Solution Approach 2:
The patent employs periodic or transient inhibition of DOT1L activity, particularly targeting the period after cardiac injury when regeneration is needed. This temporal specificity allows beneficial effects during the treatment window while avoiding chronic inhibition that could cause harmful effects.
Data Source
AI summary
This disclosure provides methods to modulate cardiac regeneration in a mammalian cardiac cell or progenitor, comprising contacting the mammalian cardiac cell with a DOT1L gene modulator.