Methods and compositions relating to MEK5 and cardiac hypertrophy and dilated cardiomyopathy
AssigneeBoard of Regents, The University of Texas System
InventorsEric N. Olson, Rebekka Nicol
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Abstract
The present invention relates to compositions and methods relating to MEK5 and its role in heart disease. This protein has now been identified as a target for therapeutic intervention due to its role molecular events that lead to or contribute to cardiac hypertrophy and/or dilated cardiomyopathy. In particular, inhibition of MEK5 activity will lead to decrease signalling of the pathways and reduce or eliminate the effects on sarcomere assembly, which in turn result or contribute to cardiac dysfunction. Also provided are transgenic animals and methods of screening for inhibitors of MEK5.
Claims64
A method for inhibiting cardiac hypertrophy in a subject comprising administering to said subject an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits cardiac hypertrophy.
A method of inhibiting cardiac myocyte elongation in a cell comprising administering to said cell an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits cardiac myocyte elongation.
A method of restoring balance between serial and parallel sarcomere assembly in a cell comprising administering to cell an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity restores the balance between serial and parallel sarcomere assembly.
A method of inhibiting ventricular wall thinning in a subject comprising administering to said subject an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits ventricular wall thinning.
A method of reducing sensitivity of MEK5 to G-protein coupled receptor (“GPCR”) agonists in a cell comprising administering to said cell an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity reduces sensitivity of MEK5 to GPCR agonists.
A method for inhibiting MEK5-induced hypertrophic signaling in a cell comprising administering to said cell an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits MEK5-induced cardiac hypertrophic signalling.
A non-human transgenic mammal, cells of which comprise a constitutively-activated MEK5 coding region under the control of a heterologous promoter, wherein said constitutively activated MEK5 is expressed in said cells.
A non-human transgenic mammal, cells of which comprise a MEK5 coding region under the control of a promoter, wherein said MEK5 is expressed in said cells.
A non-human transgenic mammal, cells of which comprise a dominant-negative MEK5 coding region under the control of a promoter, wherein said dominant-negative MEK5 is expressed in said cells.
A method of screening for an inhibitor of cardiac hypertrophy comprising:
- (a) providing a cell comprising a MEK5 coding region under the control of a promoter, wherein MEK5 is expressed therefrom;
- (b) contacting said cell with a candidate inhibitor substance;
- and
- (c) determining MEK5 activity of said cell;
- wherein a reduction in MEK5 activity in the presence of said candidate inhibitor substance, as compared to the MEK5 activity in the absence of said candidate inhibitor substance, indicates that said candidate inhibitor substance is an inhibitor of MEK5 activity, and hence, an inhibitor of cardiac hypertrophy.
A method for inhibiting dilated cardiomyopathy in a subject comprising administering to said subject an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits dilated cardiomyopathy.
A method for inhibiting heart failure in a subject comprising administering to said subject an amount of a composition effective to inhibit MEK5 activity, whereby inhibition of MEK5 activity inhibits heart failure.
Dependencies are inferred from the claim text.