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Method for regulation of telomere length

a technology of telomerase and telomere elongation, which is applied in the direction of transferases, instruments, extracellular fluid disorders, etc., can solve the problems of age-related degenerative diseases that are often fatal, tumors lacking telomerase are not able to continue to grow indefinitely, and the activity of telomerase is difficult to detect in normal somatic human tissues, so as to achieve the effect of increasing telomere elongation

Inactive Publication Date: 2018-04-26
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The activation of the ATM kinase pathway results in increased telomere elongation, providing a potential therapeutic approach for telomere-mediated diseases and cancer treatment by manipulating telomere length.

Problems solved by technology

In contrast, telomerase activity is difficult to detect in normal somatic human tissues.
Studies in mice have found that tumors lacking telomerase are not able to continue to grow indefinitely.
In humans, syndromes of telomere shortening cause age-related degenerative diseases that are often fatal.
The different methods for measuring telomeres and the small number of samples analyzed left this unresolved.
Since ATM− / − mice are sterile, it is not possible to interbreed them to examine telomere length over many generations.
Thus, the failure to see short telomeres in these mice might be simply due to the limitations of breeding.
Ataxia telangiectasia (AT) patients, who lack ATM function, have immune system defects, neurological impairment, are cancer prone and radiosensitive.
However, there have been conflicting results regarding the role of ATM in regulating telomere elongation in mammalian cells.
However, together the loss of both Tel1ATM and Mec1ATR leads to further shortening than in Tel1ATM alone.

Method used

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  • Method for regulation of telomere length
  • Method for regulation of telomere length
  • Method for regulation of telomere length

Examples

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Effect test

example 1

Addition of De Novo Initiated Telomeres Assay (ADDIT Assay) to Identify Telomere Length Regulators

[0093]To critically access the role of ATM, as well as other potential telomere length regulators, an assay was developed that measures telomere repeat addition in cells, referred to herein as the addition of de novo initiated telomeres assay, or ADDIT assay. Using the ADDIT assay, it was determined that that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.

[0094]Results

[0095]Addition of De Novo Initiated Telomeres—ADDIT Assay

[0096]To critically ac...

example 2

Role of Cyclin-Dependent Kinases in Telomere Length Regulation

[0169]Telomeres are specialized structures at the ends of the linear chromosome that allow cells to distinguish the natural ends from double-strand DNA break. Failure to maintain telomere structure can result in chromosome fusions and genomic instability. Telomere structure, and the enzyme telomerase that is responsible for synthesizing telomeric repeats, are highly conserved. Telomere DNA consists of a short tandem repeats of a short G-rich sequence with a stretch of 3′ overhang. This G-rich 3′ overhang structure of telomeres is conserved throughout eukaryotes, including ciliates, fungi and mammals. The proteins that interact with the 3′ single-strand overhang and those that bind the double-strand telomeric repeats have important roles in maintaining telomere lengths as they are involved in protecting telomere ends and modulating telomerase access to telomeres.

[0170]Most of the key players and requirements for telomere l...

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Abstract

Provided herein are methods for increasing telomere length comprising contacting a cell with an agent that activates the ataxia telangiectasia mutated (ATM) kinase pathway or a cyclin dependent kinase pathway, thereby elongating telomeres in the cell. Also provided is a method for treating disorders such as cancer and telomere syndromes.

Description

RELATED APPLICATION DATA[0001]This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Ser. No. 62 / 184,148, filed Jun. 24, 2015, and U.S. Provisional Patent Application Ser. No. 62 / 135,616, filed Mar. 19, 2015, the entire contents of which is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT[0002]This invention was made in part with government support under Grant No. AG009383 awarded by the National Institutes of Health. The United States government has certain rights in this invention.INCORPORATION OF SEQUENCE LISTING[0003]The material in the accompanying sequence listing is hereby incorporated by reference into this application. The accompanying sequence listing text file, name JHU3860_1WO_Sequence Listing, was created on ______, and is ______ kb. The file can be assessed using Microsoft Word on a computer that uses Windows OS.BACKGROUND OF THE INVENTIONField of the Invention[0004]The invention r...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/502C12Q1/6851C12Q1/686C12N9/10C12N9/12A61P7/00A61P7/06A61P11/00A61P35/00A61P17/00
CPCA61K31/502C12Q1/6851C12Q1/686C12N9/1077C12Y204/0203C12N9/12C12Y207/11022A61P7/00A61P7/06A61P11/00A61P35/00A61P17/00A61K31/4184A61K31/55A61K31/7105A61K31/711A61K31/713A61K45/06C12N15/1137C12N2310/11C12N2310/14C12N2310/141C12N2310/3231C12N2310/531A61K2300/00C12N15/86G01N33/5008
Inventor GREIDER, CAROL W.LEE, STELLA S.
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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