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An agent that enables sirt7 gene expression and the use thereof

A gene expression and agent technology, applied in the field of gene targeted therapy, can solve the problems of hardened lifespan, shortening, vascular calcification, etc.

Pending Publication Date: 2021-11-16
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recent work by two groups has shown that smooth muscle cell-specific progerin knock-in mice are healthy and have a normal lifespan but develop vascular calcification, atherosclerosis, and shortened lifespan when crossed with Apoe- / - mice (23;24)

Method used

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  • An agent that enables sirt7 gene expression and the use thereof
  • An agent that enables sirt7 gene expression and the use thereof
  • An agent that enables sirt7 gene expression and the use thereof

Examples

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example 1

[0062] Single-cell transcriptomic analysis revealed that CD31 + Four major cell clusters in mouse lung endothelial cells (MLECs)

[0063] To study the aging mechanism of vascular endothelium, we generated a conditional progerin knock-in mouse model in which Lmna G609G The mutation is flanked by loxP sites, ie Lmna f / f mice ( Figure 8 A). Will Lmna f / f Mice were crossed with E2A-Cre mice, in which Cre recombinase is ubiquitously expressed, including germ cells, to produce Lmna G609G / G609G mice. Progerin in these Lmna G609G / G609G Ubiquitously expressed in mice, it recapitulates many of the progeria features found in Progeria syndrome, including growth retardation and shortened lifespan ( Figure 8 B-D).

[0064] In order to understand the main changes in VE, we used FACS ( figure 1 A) from three pairs of Lmna G609G / G609G (G609G) and Lmna f / f (Flox) CD31 isolated from control mice + Mouse lung endothelial cells (25) were subjected to 10× Genomics single-cell RNA sequ...

example 2

[0066] Progeriatric endothelial cells exhibit a systemic inflammatory response

[0067] In four CD31 + In mouse lung endothelial cell clusters, endothelial cells and like cells showing high levels of p21 Cip1 / Waf1 ( Figure 9 A), which is a typical aging marker. This finding suggests that these cells are the main targets of progerin in the context of aging. Interestingly, a previous study reported that by incorporating Lmna f / + obtained by crossing to Lyz-Cre mice The senescence phenotype caused by specific progerin was minimal (23), implying that It may only play a minor role in the aging of the body. Therefore, we focused on endothelial cells for further analysis. We recovered 899 and 445 endothelial cells from E2A and Flox mice, respectively ( figure 2 A). Genes with expression changes >1.5-fold in these mice were selected for GO and KEGG analysis. We observed significant enrichment in pathways regulating chemotaxis, immune responses to malaria and Chagas d...

example 3

[0069] Vascular endothelial dysfunction contributes to defective vasodilation in progeria mice

[0070] In order to verify whether vascular endothelial dysfunction plays an important role in systemic aging, we will Lmna f / f Mice were crossed with the Tie2-Cre line to generate Lmna f / f ; TC mice, in which the expression of Cre recombinase is driven by the promoter / enhancer of the endothelial-specific Tie2 gene (26). Single-cell transcriptome analysis confirmed that Tie2 was mainly detected in endothelial cells ( Figure 9 B). Consistently, in Lmna f / f ; Progerin was observed in the vascular endothelium of TC mice, but not in Lmna f / f It was not observed in the vascular endothelium of control mice or other tissues ( Figure 10 ). Vascular endothelium-specific progerin induces Lmna f / f ; TC mice had intimal thickening in a manner similar to that of total KI mice i.e. Lmna G609G / G609G Mice are similar ( Figure 4 A-B). We next performed a functional analysis of the vascu...

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Abstract

Provided is an agent that enables Sirt7 gene expression, especially a recombinant adeno-associated virus(rAVV) that enables vascular endothelium(VE)-specific Sirt7 gene expression, and the use thereof. A method for improving neovascularizaiton, ameliorating aging features, extending lifespan and treating age-related diseases by using the agent especially the rAAV is also provided.

Description

technical field [0001] The present invention relates to gene targeted therapy. In particular, the present invention relates to agents that express the Sirt7 gene, which are useful for rejuvenating blood vessels, prolonging lifespan, and treating age-related diseases. [0002] technical background [0003] Aging is the greatest risk factor for many age-related diseases, such as vascular dysfunction and cardiovascular disease (CVD) (1). Blood vessels are composed of an intima (composed of endothelial cells (ECs)), a media (composed of vascular smooth muscle cells (VSMCs)) and an adventitia (composed of connective tissue) (2). The endothelium separates the vessel wall from the blood flow and has an irreplaceable role in regulating vascular tone and homeostasis (3, 4). Age-related functional decline in endothelial cells and vascular smooth muscle cells is a major cause of cardiovascular disease (4-6). Endothelial cells secrete various vasodilators and vasoconstrictors that act...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C12N5/10A61P3/00A61P9/00
CPCA61P9/00A61P3/00C12N2750/14143A01K67/0278A01K2217/072A01K2227/105A01K2267/035C12N2800/30C12N15/86
Inventor 刘宝华孙世民唐小龙
Owner SHENZHEN UNIV
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