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CAMKII-delta9 antagonists and uses thereof

An antagonist and antibody technology, applied in the field of biomedicine, can solve problems such as the unknown DNA of cardiomyocytes

Pending Publication Date: 2022-04-29
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the mechanisms underlying DNA repair in cardiomyocytes remain largely unknown

Method used

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  • CAMKII-delta9 antagonists and uses thereof
  • CAMKII-delta9 antagonists and uses thereof
  • CAMKII-delta9 antagonists and uses thereof

Examples

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Embodiment approach

[0187] The biological materials used in all examples, various cloning and expression plasmids, culture medium, enzymes, buffers, and various culture methods, protein extraction and purification methods, and other molecular biology manipulation methods are all those skilled in the art well known. For more details, please refer to "Molecular Cloning: A Laboratory Manual" (Cold Spring Harbor, 1989) edited by Sambrook et al. and "Short Protocols in Molecular Biology" (Frederick M. ), 1998).

[0188] General Methods and Materials

[0189] 1.1 Animals

[0190] Animals were housed at the Laboratory Animal Center of Peking University, China (a laboratory animal facility certified by the Association for Assessment and Accreditation of Laboratory Animal Care). Animals were randomly assigned to experimental groups. Only use male animals. In our study, no non-inclusion or exclusion parameters were used. Researchers were not blinded to treatment, but subjective assessments were not...

Embodiment 1

[0262] Example 1. Presence of CaMKII-δ9 in Human Heart

[0263] The present inventors performed single-molecule real-time (SMRT) sequencing (Pacific Biosciences) on myocardial tissues of mice, rats, rhesus monkeys, and humans (Sharon, D. et al., Nature biotechnology 31, 1009-1014, doi: 10.1038 / nbt.2705(2013)) to detect the concentration of splice variants of CaMKII-δ. Library preparation, sequencing, and data collection for SMRT sequencing are described in Section 1.3 of General Methods and Materials. Quantification of CaMKII-δ splice variants was performed according to the method described in Section 1.7 of General Methods and Materials.

[0264] Surprisingly, the inventors found that the well-studied splice variant CaMKII-δ2 is extremely low in rhesus monkey (3.1%) and human (6.3%) hearts, although it is Cardiac CaMKII-δ accounted for 29% and 22.5% of the total transcripts, respectively. The previously reported but functionally overlooked CaMKII-δ9 became a very abunda...

Embodiment 2

[0267] Example 2. The up-regulation of CaMKII-δ9 is related to various heart diseases

[0268] To investigate the pathological relevance of CaMKII-δ9, the inventors first assessed its levels in several models of cardiac injury. To simulate hemodynamic pressure overload, the inventors performed transverse thoracic constriction (TAC) surgery on mice. The experimental methods, animals, and materials used in this example are described in sections 1.1, 1.2, 1.4, 1.15, 1.18, 1.19, 1.26, and 1.27 of General Methods and Materials.

[0269] After exposure to the chemotherapeutic drug doxorubicin (Dox; 1 μM) or H 2 o 2 (200 μM) in NRVM under oxidative stress, the expression of CaMKII-δ9 was significantly increased ( figure 1 e, f). Compared with the sham group, the protein level of CaMKII-δ9 was significantly increased in TAC hearts ( figure 1 g). More importantly, in the myocardial tissue of patients with hypertrophic cardiomyopathy (HCM), CaMKII-δ9 was significantly elevated r...

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Abstract

Provided are methods of treating or preventing Ca2 + / calmodulin-dependent kinase II (CaMKII) mediated diseases, methods of reducing heart damage, methods of stimulating the activity of an ubiquitin-binding enzyme, methods of preventing degradation of an ubiquitin-binding enzyme, methods of preventing cardiac muscle cell death, methods of reducing DNA damage in a cell, methods for diagnosing CaMKII mediated diseases, and methods of treating or preventing CaMKII mediated diseases. The invention relates to CaMKII (CaMKII)-mediated diseases, a kit for diagnosing the CaMKII-mediated diseases, a biomarker for diagnosing the CaMKII-mediated diseases, and application of CaMKII delta 9 as the biomarker for diagnosing the CaMKII-mediated diseases. Also provided herein are methods for identifying molecules, isolated polypeptides, isolated nucleic acids, and antagonists thereof.

Description

technical field [0001] The present invention relates to the field of biomedicine. In particular, the present invention relates to CaMKII-δ9 antagonists and uses thereof. Background technique [0002] Throughout the lifespan of an organism, the genome is constantly under attack from a variety of internal and external stress signals, resulting in DNA damage. Excessive DNA damage compromises genome integrity and hinders DNA replication and transcription (Campisi, J. & d'Adda di Fagagna, F. Nature reviews. Molecular cell biology 8, 729-740, doi: 10.1038 / nrm2233 (2007)). DNA repair acts as a protective measure against unwanted DNA damage, thereby maintaining genome stability and cell viability. Aberrant DNA repair leads to accumulation of DNA damage and instability of the genome, leading to cell death. Because mammalian cardiomyocytes have little regenerative capacity, loss of terminally differentiated cardiomyocytes is a common cause of many types of cardiac disease, includin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K38/18
CPCA61K38/00G01N33/573G01N2333/91215G01N2800/32G01N2500/02C12Q1/485G01N2333/075
Inventor 张茂张岩肖瑞平高华
Owner PEKING UNIV
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