Transgenic Mouse Model for NASH-Induced HCC Progression

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Solution Overview

Problem

Current models fail to effectively study the progression of non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) and test treatments for prevention or amelioration, as existing animal models do not accurately replicate human NASH-related HCC development.

Innovation Solution

A genetically modified non-human animal model, such as a transgenic mouse with the MUP-uPA gene, is created by transplanting HCC progenitor cells and subjecting them to a high-fat diet, allowing for the induction of HCC-like symptoms and the evaluation of treatment efficacy through modulation of TNF, p62, NRF2, mTORC1, and c-Myc expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing animal models are used to study NASH progression to HCC, then research can be conducted, but the models do not accurately replicate human NASH-related HCC development

Engineering Contradiction:

Improveaccuracy of model replicationVSAvoidapplicability to human NASH-HCC progression

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent uses HCC progenitor cells as an intermediary element to bridge the gap between normal liver tissue and full-blown HCC. These progenitor cells serve as a mediator that, when transplanted into mice with NASH, accurately replicate the human disease progression from NASH to HCC, solving the problem of model accuracy while maintaining versatility for studying human-specific disease mechanisms

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If a high-fat diet is administered to induce NASH in animal models, then NASH symptoms develop, but the progression to HCC is not effectively replicated

Engineering Contradiction:

Improvepresence of NASH symptomsVSAvoidprogression to HCC

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies preliminary action by first inducing NASH through high-fat diet, then subsequently transplanting HCC progenitor cells to trigger HCC progression. This two-step preliminary preparation ensures that the animal model first develops NASH symptoms and then progresses to HCC, accurately replicating the human disease sequence and improving reliability of HCC progression studies

Inventive Principle:

Principle #10Preliminary action

3Productivity

If traditional animal models are used to test treatments for NASH-HCC, then treatment evaluation can be performed, but specific therapeutics for NASH-driven HCC cannot be effectively identified

Engineering Contradiction:

Improvetreatment evaluation capabilityVSAvoidefficacy detection accuracy

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The patent implements feedback mechanisms by using transgenic mice with reporter genes that provide real-time information about HCC development and treatment response. The reporter systems give visual and measurable feedback on tumor progression and treatment efficacy, enabling precise measurement of therapeutic effects and accelerating the identification of effective NASH-HCC treatments

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS10034462B2Animal model of nash-induced hepatocellular carcinoma and methods for developing specific therapeutics

Publication Date: 2018.07.31 RGT UNIV OF CALIFORNIA

AI summary

The invention provides a non-human animal model for non-alcoholic steatohepatitis (NASH)-induced heptocellular carcinoma, methods of screening for agents for treating heptocellular carcinoma, methods of screening for targets useful in suppressing NASH progression to heptocellular carcinoma, methods of treating heptocellular carcinoma, and compositions for treating the same.