VGLL4 UCP-1 Cis-Regulatory Element for BAT-Specific Expression
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Solution Overview
Problem
Current compositions and methods for increasing brown adipose tissue (BAT) are lacking, hindering effective pharmacological therapies for obesity and related pathologies such as diabetes and liver disease.
Innovation Solution
A polynucleotide construct comprising a cis-regulatory element and a nucleotide sequence encoding a vestigial like 4 protein (Vgll4) is used, specifically driving expression in BAT and liver cells, with optional amino acid substitutions in TDU domains to enhance mitochondrial gene expression and inhibit lipogenesis, delivered via a viral vector.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional methods are used to treat obesity, then some therapeutic effects may be achieved, but compositions and methods for increasing brown adipose tissue are lacking
Solution Approach 1:
The invention divides the therapeutic approach into specific molecular components: a cis-regulatory element (enhancer and promoter) that controls spatial and temporal expression of Vgll4, and the Vgll4 coding sequence itself. This segmentation allows precise delivery to brown adipose tissue through viral vectors, enabling targeted increase of BAT volume without affecting other tissues.
Solution Approach 2:
The invention uses a viral vector as an intermediary to deliver the polynucleotide construct containing the cis-regulatory element and Vgll4 coding sequence into brown adipose tissue cells. This intermediary enables efficient transduction and expression of Vgll4, which then mediates the increase in BAT volume and metabolic improvements.
2Quantity of substance
If Vgll4 is overexpressed without tissue-specific regulation, then protein levels increase, but expression occurs in wrong tissue types
Solution Approach 1:
The invention applies local quality by using a tissue-specific cis-regulatory element that confers brown adipose tissue-specific expression to the Vgll4 gene. The enhancer and promoter sequences are selected to be active specifically in BAT cells, ensuring that Vgll4 protein is produced only in the desired tissue location with appropriate levels, while remaining absent or low in other tissues.
Data Source
AI summary
Provided is a polynucleotide, including a cis-regulatory element and a nucleotide sequence encoding a vestigial like 4 protein, wherein the cis-regulatory element includes an uncoupling protein 1 enhancer and an uncoupling protein 1 promoter. Also provided is a viral vector including said polynucleotide. Also provided is a method of transfecting a cell or a subject with said polynucleotide or said viral vector.