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Modulation of tjp1 expression to regulate regeneration of heart cells

A technology of heart disease, neuregulin, applied in the field of biochemistry

Active Publication Date: 2019-08-23
AGENCY FOR SCI TECH & RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, treatments that allow survival or replace lost CM after MI would have enormous economic and social impact

Method used

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  • Modulation of tjp1 expression to regulate regeneration of heart cells
  • Modulation of tjp1 expression to regulate regeneration of heart cells
  • Modulation of tjp1 expression to regulate regeneration of heart cells

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Experimental program
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Embodiment

[0060] Tight junction protein 1 (Tjp1), also known as Zonula Occludens-1 (ZO-1), is an actin-binding scaffold protein localized to the intercalated disc in the CM. This plasma membrane subdomain contains N-cadherin-based adherens junctions, desmosomes, and gap junctions, and provides mechanical and electrical coupling between CMs. Tjpl binds α-catenin bound to N-cadherin as well as Cx-43. Tjp1 regulates self-renewal and differentiation of mouse ES cells, and Tjp1-deficient mice display early embryonic lethality. Little is known about the functional role of Tjp1 in CM. Tjp1 associates with Cx43 after gap junction internalization during MI-induced cardiac remodeling. Expression of a peptide encoding the first two PDZ domains of Tjp1 leads to abnormal subcellular architecture of adherens and gap junctions in rat ventricular CMs. Tjp1 levels studied with human HF showed lower Tjp1 levels in failing hearts but upregulation in dilated and ischemic cardiomyopathy.

[0061] Here, ...

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Abstract

The invention is a method for treating a heart disease, in particular acute myocardial infarction (AMI) in a subject comprising the step of administering to the subject a Tjp1 inhibitor, wherein administration of said Tjp1 inhibitor promotes cardiomyocyte proliferation. The invention further includes use of Tjp1 inhibitor in the manufacture of a medicament for a heart disease, a patch, and a nucleic acid encoding a Tjp1 inhibitor. In a particular embodiment, the Tjp1 inhibitor is a nucleic acid, i.e. an siRNA or shRNA of Tjp1. The invention also includes administration of said Tjp1 inhibitor in combination with Neuregulin-1 (NRG1 ), Fibroblast growth factor (FGF), Vascular endothelial growth factor (VEGF) or Follistatin-like 1 (Fst1 ) and wherein said inhibitor is delivered in an adeno-associated virus of serotype 9 (AAV 9).

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority from Singapore Provisional Application No. 10201607673U filed on 14 September 2016, the contents of which are hereby incorporated by reference in their entirety for all purposes. technical field [0003] The present invention relates generally to biochemistry. In particular, the invention relates to methods of treating heart disease by targeting Tjp1. Background technique [0004] Modern sedentary lifestyles, diets, increased life expectancy and increases in diseases such as diabetes have led to an explosion of patients suffering from cardiovascular diseases, including acute myocardial infarction (AMI). Contemporary treatments, including angioplasty, stenting, and adjuvant medical therapy, have reduced early mortality in AMI. However, despite particular adherence to guideline-recommended therapy, the local 28-day AMI case fatality rate in 2010 significantly exceeded the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/713C12N15/113A61P9/10
CPCA61K31/713C12N15/113A61P9/10C12N2310/14C12N2310/531A61K35/761A61K38/1709A61K38/1825A61K38/1866A61K38/1883C12N2310/11C12N2310/122C12N2310/341A61K38/1808A61K38/1841C12N15/1138A61K31/7088
Inventor W·亨齐克徐建良王炯伟P·J·考莎丽雅
Owner AGENCY FOR SCI TECH & RES
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