Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression

• US 7,420,100 B2
• Filed: 08/08/2003
• Issued: 09/02/2008
• Est. Priority Date: 08/20/1999
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Olson, Eric N., Lu, Jianrong, McKinsey, Timothy
• Primary Examiner(s): Sullivan; Daniel M
• Application Number:
  US10/637,403
• Publication Number:
  US 20050106654A1
• Time in Patent Office: 1,852 Days
• Field of Search: None
• US Class Current: 800/18
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Q 1/44 involving esterase
• CPC Class Codes: G01N 2333/4712 Muscle proteins, e.g. myosin, actin, protein
• CPC Class Codes: G01N 2333/916 acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 33/6887 from muscle, cartilage or connective tissue

Abstract

The present invention relates to cardiac hypertrophy. More particularly, the present invention defines the molecular events linking calcium stimulation to cardiac hypertrophy. More specifically, the present invention shows that Ca²⁺ stimulation of the hypertrophic response is mediated through an HDAC 4 and 5 interaction with MEF2, and that phosphorylation of HDACs results in loss of HDAC-mediated repression of MEF2 hypertrophic action. Thus, the present invention provides methods and compositions of treating cardiac hypertrophy, as well as methods and compositions for identifying subjects at risk for cardiac hypertrophy. Further provided are methods for the detection of compounds having therapeutic activity toward cardiac hypertrophy.

Claims

1. A transgenic mouse lacking one or more functional alleles of histone deacetylase (HDAC) 5, wherein said transgenic mouse exhibits a substantially increased probability of developing cardiac hypertrophy as compared to a littermate that does not lack one or more functional alleles of HDAC5.

2. The transgenic mouse of claim 1, further comprising a detectable marker gene under the control of a myocyte enhancer factor-2 (MEF2) regulated promoter.

3. The transgenic mouse of claim 2, wherein said MEF2 regulated promoter is a Nur77 gene (NGFI-B) promoter.

4. The transgenic mouse of claim 2, wherein said detectable marker gene is selected from the group consisting of β

-galactosidase, luciferase and GFP.

5. The transgenic mouse of claim 1, wherein said transgenic mousc lacks both functional alleles of HDAC5.