Metabolic Modulation of NRSE Gene Expression via NADH

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods lack effective ways to modulate gene expression for diseases like epilepsy, cancer metastasis, and cardiac hypertrophy, particularly for genes regulated by the Neuron Restrictive Silencing Element (NRSE)/Neural Restrictive Silencing Factor (NRSF) system, and there is a need to link cellular metabolism to gene expression regulation.

Innovation Solution

Influencing the redox charge in cells by altering the concentrations of NAD+ and NADH, using compounds that inhibit or reduce glycolysis, such as 2-deoxyglucose, to modulate gene expression by repressing or de-repressing genes regulated by NRSE/NRSF promoters, thereby affecting cellular phenotype and disease states.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional methods are used to modulate gene expression, then existing gene regulation mechanisms (cis and trans elements) can be targeted, but there is a lack of effective ways to modulate expression of NRSE/NRSF regulated genes associated with diseases like epilepsy, cancer metastasis, and cardiac hypertrophy

Engineering Contradiction:

Improveeffectiveness of gene expression modulationVSAvoidability to modulate NRSE/NRSF regulated genes

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention changes the chemical parameter of cellular redox state by administering oxidizing agents (increasing NAD+) or reducing agents (increasing NADH) to modulate the activity of NRSF transcription factor and thereby control expression of NRSE-regulated genes associated with disease

Inventive Principle:

Principle #35Parameter changes

2Reliability

If glycolysis is inhibited to increase NAD+ and modulate gene expression, then therapeutic benefits are achieved, but cellular energy metabolism is altered

Engineering Contradiction:

Improvetherapeutic effect on diseaseVSAvoidcellular energy metabolism

Core Design Contradiction:

ReliabilityVSUse of energy by moving object

Solution Approach 1:

The invention uses redox-active compounds (oxidizing agents or reducing agents) as intermediaries to modulate the NAD+/NADH ratio and thereby control NRSF activity and gene expression, rather than directly inhibiting glycolysis or targeting NRSF itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach allows for metabolic modulation of gene expression, providing therapeutic benefits for neurological disorders, cancer, and cardiac conditions by changing the expression of genes implicated in these diseases, as demonstrated by increased seizure threshold in epilepsy models and altered gene expression profiles.

Implementation Method 1

using compounds that inhibit or reduce glycolysis, such as 2-deoxyglucose, to modulate gene expression by repressing or de-repressing genes regulated by NRSE/NRSF promoters

Methodology Applied

Scientific EffectGlycolysis: Fermentation

Implementation Method 2

Influencing the redox charge in cells by altering the concentrations of NAD+ and NADH

Methodology Applied

Scientific EffectRedox reactions: Redox Reactions

Data Source

PatentUS7557085B2Metabolic-based methods for modulating gene expression

Publication Date: 2009.07.07 WISCONSIN ALUMNI RES FOUND

AI summary

This invention provides methods for modulating cellular gene expression for genes operably linked to an NRSE element that is recognized by an NRSF transcriptional repressor, by changing the concentration of reduced nicotinamide adenine dinucleotide (NADH) in the cell.