Medical application of ubiquitin-specific proteases USP 7 to treating aging and related diseases

A protease and aging technology, applied to the medical use of ubiquitin protease USP7 in aging and related diseases, the field of preparation of drugs for preventing and treating aging-related diseases, can solve problems such as telomere damage, telomere shortening, cell aging, etc., and achieve tumor inhibition. The effect of development and prevention of telomere protein degradation

Active Publication Date: 2018-06-12
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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  • Medical application of ubiquitin-specific proteases USP 7 to treating aging and related diseases
  • Medical application of ubiquitin-specific proteases USP 7 to treating aging and related diseases
  • Medical application of ubiquitin-specific proteases USP 7 to treating 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 respiratory function. Lung tissue RNA was extracted, real-time quantitative PCR was used to detect the mRNA expression of USP7, TPP1, HP1g, SPC, -SMA, T1, Col6a and s100a4; lung tissue paraffin-embedded sections, Masson and H&E staining were used to detect the expression of lung type II cells by immunofluorescence Percentage (SPC p...

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Abstract

The invention provides application of ubiquitin-specific proteases USP7 to preparing drugs for treating aging and related diseases. The amino acid sequence of the USP7 is shown as SEQ. NO.2. Accordingto the application of the ubiquitin-specific proteases USP7 to preparing the drugs for treating aging and related diseases, the USP7 is activated to avoiding degradation of telomere proteins and damage of telomeres, particularly degradation of telomere proteins in environmental stress states such as radiation damage or oxidative stress., and meanwhile, avoid telomere damage and shortening, tissueand organ aging and related diseases caused by pressurized or stressed anaerobic states; expression and enzyme activity of the USP7 is inhibited to prevent protecting effects of the USP7 on the telomere proteins and the telomeres, to lead to telomere shortening and damage response, and further to cause proliferation and growth inhibition, aging and death of tumor cells and inhibit generation, development, growth, infiltration and metastasis of tumor. The USP7 can be applied to preparing drugs for preventing and treating telomere function related diseases and provide new anti-aging thoughts and methods.

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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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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