Inducible Neuron-Specific HuR Knockout Mouse Model
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Solution Overview
Problem
Current models lack a specific genetic animal that targets neuronal cells to simulate ALS and its related molecular signatures, hindering the investigation of HuR's role in neurons and the development of effective ALS treatments.
Innovation Solution
The creation of inducible neuron-specific HuR-deficient mice using a neuron-specific promoter and Cre recombinase, which mediates the deletion of the HuR gene upon tamoxifen induction, resulting in a phenotype resembling ALS, allowing for the study of HuR's function and potential therapeutic interventions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a general HuR knockout model is used, then HuR function can be studied, but neuron-specific function cannot be isolated from other cell types
Solution Approach 1:
The patent applies local quality by making the HuR knockout specific to neuronal cells while leaving other cell types unaffected. This is achieved through the use of a neuron-specific promoter (Thy1 promoter) that drives Cre recombinase expression only in neurons, thereby deleting the HuR gene specifically in neuronal tissue while preserving HuR expression in non-neuronal cells.
2Loss of time
If a constitutive knockout model is used, then HuR's overall role can be assessed, but temporal progression of neuronal degeneration cannot be studied
Solution Approach 1:
The patent applies preliminary action by pre-establishing the inducible knockout system in transgenic mice before the actual experiment begins. The mice carry both the floxed HuR allele and the Thy1-Cre-ERT2 transgene, but the actual gene deletion is triggered only when tamoxifen is administered, allowing researchers to control the timing of HuR loss and observe temporal progression of neuronal degeneration.
3Reliability
If HuR is completely deleted in neurons, then neuronal function loss can be studied, but compensatory mechanisms may be masked
Solution Approach 1:
The patent applies parameter changes by controlling the extent of HuR deletion through inducible Cre recombinase activation. By adjusting tamoxifen dosage and timing, researchers can achieve complete or partial HuR deletion, allowing study of both severe phenotypes and subtle compensatory mechanisms that might occur with partial loss of HuR function.
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
The HuR-deficient mice exhibit motor deficits and neuronal cell death, mirroring ALS pathology, providing a valuable model for drug screening and understanding ALS mechanisms, and potentially leading to the identification of effective treatments.
Implementation Method 1
the genetic construct further comprises at least one recombinase sequence inducible by an exogenous agent, wherein the recombinase sequence, once induced, mediates the deletion of the HuR gene in the transgenic animal
Data Source
AI summary
Provided herein non-human transgenic animals comprising a genome that: i) under-expresses, or is inducible to under-express, Hu Antigen R (HuR) in at least some neurons of said transgenic animal; ii) does not express HuR, or is inducible to not express HuR, in at least some neurons of said transgenic animal; or iii) does not express functional HuR, or is inducible to not express functional HuR in at least some neurons of said transgenic animal, as well as methods of screening drugs and therapies (e.g., useful in treating ALS) using such animals.