SRF-Targeting Agents for Diastolic Heart Failure Screening
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Solution Overview
Problem
Current treatments for heart failure with diastolic impairment, characterized by increased left ventricular wall thickness and reduced diastolic function, lack effective methods to mitigate these symptoms, particularly as they relate to serum response factor (SRF) expression and its impact on cardiac tissue.
Innovation Solution
The development of transgenic mice models with mild overexpression and reduction of SRF, which mimic normal cardiac aging and heart failure symptoms, to identify agents that bind to SRF, prevent SRF binding to serum response elements, or reduce SRF protein levels, offering potential therapeutic candidates for treating diastolic impairment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If SRF expression is reduced to prevent diastolic impairment, then cardiac function is maintained, but SRF binding to SRE is prevented which may affect normal cardiac development and function
Solution Approach 1:
The mutant SRF protein is designed to have localized functionality - it retains the ability to bind to wild-type SRF and form dimers, but loses the ability to bind to SRE DNA sequences. This local quality change allows the mutant to interfere with wild-type SRF function specifically at the DNA binding interface without completely abolishing SRF dimerization capability, thereby selectively preventing harmful SRF-SRE binding while maintaining essential SRF protein-protein interactions
Solution Approach 2:
The mutant SRF acts as an intermediary that binds to wild-type SRF proteins and prevents them from binding to SRE DNA sequences. The mutant SRF serves as a molecular mediator that sequesters wild-type SRF in non-functional dimers, thereby indirectly preventing the harmful effect of excessive SRF-SRE binding that leads to diastolic impairment, while allowing wild-type SRF to potentially perform other non-DNA binding functions
2Adaptability or versatility
If transgenic mice models are developed to screen for SRF-targeting agents, then potential therapeutic candidates are identified, but the complexity of the screening process increases
Solution Approach 1:
The screening approach is segmented into distinct components: (1) transgenic mouse models with controlled SRF expression levels, (2) isolated SRF binding assays using the mutant SRF protein, and (3) in vivo efficacy testing in diastolic impairment models. This segmentation allows each component to be optimized independently and enables the screening process to be performed at multiple levels, from simple in vitro binding assays to comprehensive in vivo studies, thereby managing complexity while maintaining versatility
Solution Approach 2:
The mutant SRF protein serves multiple functions in the screening process: it acts as a diagnostic tool to identify SRF-binding compounds in vitro, serves as a molecular probe to assess compound specificity, and enables the creation of transgenic models for in vivo screening. This multi-functionality allows a single molecular tool to support various screening approaches, reducing the need for multiple separate systems and thereby managing complexity while enhancing adaptability
Data Source
AI summary
The invention provides a method of identifying candidate agents to test for treating heart failure involving diastolic impairment, the method comprising: testing an agent to determine whether it (a) binds to serum response factor (SRF), (b) reduces SRF binding to a serum response element (SRE), or (c) reduces SRF protein levels in a cell; wherein if the agent does one or more of (a), (b), and (c), it is identified as a candidate agent.