Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
1998-12-18
2001-02-27
LeGuyader, John L. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C800S008000, C800S009000, C800S018000, C435S320100
Reexamination Certificate
active
06194632
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to transgenic mice which express CREB. These transgenic mice provide a genetic model of dilated cardiomyopathy.
Congestive heart failure (CHF) is a leading cause of cardiovascular morbidity and mortality affecting more than 4 million Americans and representing the most common reason for hospitalization of patients over the age of 65 (1, 2). Idiopathic dilated cardiomyopathy (IDC), a primary myocardial disease of unknown etiology characterized by ventricular dilatation and depressed myocardial contractility is an important cause of CHF with an estimated prevalence of 36 cases/100,000 (3-7). Relatively little is known about the molecular mechanisms underlying the pathogenesis of IDC. Progress in this area has been limited by the lack of animal models that closely resemble the anatomical and clinical features of the human disease.
Several previously described genetically modified mice have been reported to develop cardiomyopathies. These include mice expressing mutant forms of
-myosin heavy chain (
-MHC), mice engineered to ectopically express the myf5 bHLH transcription factor in the heart, and mice containing targeted mutations of the muscle LIM protein (MLP) (49-51). However, the phenotypes of each of these mice differs significantly from that of the transgenic mice described herein. Unlike the transgenic mice of the present invention, which display progressive cardiac dilatation without hypertrophy, the
-MHC and myf5 mice develop a hypertrophic cardiomyopathy with myocyte disarray and interstitial fibrosis (50, 51). Consistent with these histological findings, the
-MHC mice display normal end systolic LV pressures and dP/dtmax but abnormal LV relaxation. These findings are highly reminiscent of the phenotype of patients with hypertrophic as opposed to dilated cardiomyopathy. The phenotype of the transgenic mice of the present invention also differed significantly from that of the recently described muscle LIM protein (MLP)-deficient mice which display soft, markedly hypertrophic hearts with grossly abnormal sarcomere structure within the first several weeks after birth (49). Unlike the transgenic mice of the present invention, 50-70% of the MLP-deficient mice die before 10 days of age.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a transgenic mouse, which displays progressive cardiac dilatation without hypertrophy.
The inventor of the present application has now achieved these and other aims by overexpressing a transgene encoding CREB or by expressing a transgene encoding a dominant negative CREB molecule in mice.
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Brinks Hofer Gilson & Lione
LeGuyader John L.
Stroup Carrie
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