Medicinal uses of the ubiquitin protease usp7 in aging and related diseases

A technology of protease and aging, which is applied in the preparation of drugs for the prevention and treatment of aging-related diseases, and the medical application field of ubiquitin protease USP7 in aging and related diseases, which can solve problems such as telomere damage, telomere shortening, and cell aging

Active Publication Date: 2021-05-04
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Degradation of TPP1 may lead to telomere damage, telomere shortening, and cell senescence

Method used

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  • Medicinal uses of the ubiquitin protease usp7 in aging and related diseases
  • Medicinal uses of the ubiquitin protease usp7 in aging and related diseases
  • Medicinal uses of the ubiquitin protease usp7 in aging and related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 USP7 binds to TPP1 at the telomere

[0018] Experimental objects: HT1080 cells, 293T cells and Hela cells.

[0019] Experimental method: HT1080 cells with stable and low expression of 17 deubiquitinases were constructed using lentivirus, and the cell cycle distribution was detected by flow cytometry; 293T cells were transfected with HA-tagged TPP1 and Flag-tagged deubiquitinases, transfected After 36 hours of transfection, the combination of deubiquitinase and TPP1 was detected by co-immunoprecipitation; the binding of deubiquitinase and telomeric DNA was detected by chromatin immunoprecipitation; USP7 was detected by immunofluorescence and FISH in Hela cells Binding to telomeres and TPP1.

[0020] The results showed that: among the 17 deubiquitinating enzymes screened ( Figure 1A ), USP7 specifically binds to TPP1 and telomeric DNA ( Figure 1B -D). Although only 20% of USP7 co-localized with telomeres, more than 90% of USP7 co-localized with TPP1 ( Fig...

Embodiment 2

[0021] Example 2 USP7 regulates TPP1 ubiquitination degradation and cell senescence

[0022] Experimental objects: HT1080 cells and Hela cells with stable and low expression of USP7.

[0023]Experimental method: Use lentivirus to construct HT1080 cells with stable and low expression of USP7, and detect the expression of TPP1 by immunofluorescence; use flow cytometry to detect cell cycle distribution and -gal staining to detect cell senescence; HT1080 cells are irradiated with X-rays, and real-time Quantitative PCR and western blotting to detect the mRNA and protein expression of FBW7, TPP1 and USP7; Hela cells were transfected with siRNA against FBW7 and USP7 to inhibit their expression, real-time quantitative PCR was used to detect the interference efficiency of USP7 and FBW7; immunofluorescence was used to detect TPP1 The expression of TPP1 and HA-tagged ubiquitin and siRNA of FBW7 or USP7 were co-transfected in 293T cells, and the ubiquitination of TPP1 was detected by co-i...

Embodiment 3

[0025] Example 3 USP7 overcomes stress-induced lung aging and fibrosis

[0026] Experimental subjects: 12 wild-type mice aged 3-6 months.

[0027] Experimental method: Take 12 wild-type mice, divide them into 4 groups, 3 mice in each group, and carry out the following treatments respectively, the trachea is infused with control or USP7 lentivirus, and the trachea is infused with PBS or bleomycin. The specific method: perfusion on the first day The control or USP7 lentivirus was perfused with PBS or bleomycin on the second day, and the control or USP7 lentivirus was perfused every 4 days thereafter. On the 22nd day, the mice were intubated to detect the respiratory function. Extract lung tissue RNA, detect the mRNA expression of USP7, TPP1, HP1g, SPC, -SMA, T1, Col6a and s100a4 by real-time quantitative PCR; lung tissue paraffin-embedded sections, Masson and H&E staining, use immunofluorescence to detect lung type II cells Percentage (number of SPC positive cells) and -SMA exp...

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Abstract

The invention provides the application of ubiquitin protease USP7 in the preparation of medicines for preventing and treating aging-related diseases. The amino acid sequence of the ubiquitin protease USP7 is shown in SEQ.No.2. The invention activates USP7 enzyme, prevents telomere protein degradation and telomere damage, especially in environmental stress state such as radiation damage or oxidative stress caused by telomere protein degradation, and prevents telomere protein degradation caused by stress or stress hypoxia. Damage shortening, aging of tissues and organs and related diseases. Inhibit the expression or enzyme activity of USP7, prevent the protective effect of USP7 on telomere protein and telomere, cause telomere shortening and damage response, thereby causing tumor cell proliferation, growth inhibition and aging death, and can inhibit tumor development, growth, invasion and metastasis . It can be applied in the preparation of drugs for preventing and treating diseases related to telomere dysfunction, and the invention provides new ideas and means for anti-aging.

Description

technical field [0001] The invention belongs to biotechnology, and relates to the medical application of ubiquitin protease USP7 protein expression, in particular to the medical application of ubiquitin protease USP7 in aging and related diseases. use. Background technique [0002] Aging-related chronic diseases such as pulmonary fibrosis and skin fiber damage are caused by telomere DNA damage and cell aging. Progressive shortening of chromosomal telomere damage is a well-recognized mechanism leading to cellular senescence. Stress, DNA breaks caused by chemicals such as radiation exposure and antibiotics, and oxidative stress accelerate shortening of telomere damage and cause premature aging, but how stress causes shortening of telomere damage and thus premature aging for decades The mechanisms of aging and related diseases are poorly understood. As diseases related to premature aging, the etiology of idiopathic pulmonary fibrosis and congenital dyskeratosis syndrome are ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/48A61P39/06A61P11/00A61P1/16A61P13/12A61P7/00A61P7/06A61P37/04A61P15/08A61P19/02A61P19/10A61P9/10A61P9/00A61P25/00A61P3/10A61P17/00A61P35/00
CPCA61K38/4873
Inventor 刘俊平王丽辉李果陈如萍
Owner HANGZHOU NORMAL UNIVERSITY
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