MSP-5 nucleic acid molecules and uses therefor

Details MSP-5 nucleic acid molecules and uses therefor MSP-5 nucleic acid molecules and uses therefor

1998-09-29

2001-03-20

Low, Christopher S. F. (Department: 1653)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S069100, C435S252300, C435S320100, C435S325000, C530S324000, C530S350000, C530S330000, C530S329000, C530S326000, C536S023100, C536S023500, C536S022100

Reexamination Certificate

active

06204013

ABSTRACT:

BACKGROUND OF THE INVENTION
Congestive heart failure is a complex clinical syndrome characterized by exertional dyspnea, fatigue and, often, peripheral edema resulting from left ventricular dysfunction. The manifestation of congestive heart failure occurs secondary to a great variety of cardiac or systemic disorders that share a temporal or permanent loss of cardiac function. Recent progress in epidemiologic research has enabled the clear delineation of the predominant etiologic factors of congestive heart failure in Western societies. In particular, the long-term follow-up in the Framingham Heart Study has demonstrated that the majority of cases was predicted by one or more of four conditions: arterial hypertension, coronary artery disease, diabetes mellitus, and left ventricular hypertrophy (Levy D. et al. (1996)
JAMA
275:1557-1562). In fact, the population attributable risk of these four factors combined accounted for about 90% of all cases with congestive heart failure.
Left ventricular hypertrophy as a complication of long-standing hypertension is a common factor in heart failure, even though the patient's blood pressure may be normal at the time congestive heart failure is diagnosed. In the absence of coronary artery disease and myocardial infarction, the left ventricular dysfunction in patients with hypertension often is predominantly a diastolic dysfunction with well-preserved chamber size and a normal ejection fraction.
Coronary artery disease is the most common etiology for left ventricular systolic dysfunction. Coronary artery disease (CAD) is a condition in which the heart muscle receives an inadequate amount of blood because of an interruption of its blood supply. It is presently the leading cause of death in the United States. Depending on the degree of interruption, symptoms can range from a mild chest pain to a full-scale heart attack. Generally, symptoms manifest when there is about a 75 percent narrowing of coronary artery lumina.
Stenotic and regurgitant valvular deformities, such as valvular stenosis, have also been well documented as contributing factors in ventricular dysfunction. Valvular stenosis is a narrowing, or stenosis, of one of the valves regulating blood flow in the heart. Stenosis may occur in the valve itself, most commonly in the mitral valve from rheumatic fever. All stenoses increase stress on the heart by making it work harder to push the blood through the abnormally narrow valve openings. As a result of mitral stenosis, blood pressure is increased. Angina pectoris and heart failure may accompany this disorder.
Finally, many diseases and toxins which directly affect the myocardium, can cause ventricular dysfunction. For example, excessive consumption of alcohol, diabetes mellitus and viral infections are associated with some causes of cardiomyopathy, whereas other cases may be genetic or idiopathic in nature.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel nucleic acid molecules which encode proteins, referred to herein as “Myocardium Secreted Protein-5” (“MSP-5”) proteins. The MSP-5 nucleic acid and protein molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes, e.g., cardiac cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding MSP-5 proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of MSP-5-encoding nucleic acids.
In one embodiment, an MSP-5 nucleic acid molecule of the invention is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to the nucleotide sequence (e.g., to the entire length of the nucleotide sequence) shown in SEQ ID NO:1, SEQ ID NO:3, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 209886, or a complement thereof. In a preferred embodiment, an MSP-5 nucleic acid molecule of the invention is at least 60% or more homologous to the nucleotide sequence (e.g., to the entire length of the nucleotide sequence) shown in SEQ ID NO:1, SEQ ID NO:3, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 209886, or a complement thereof. In a preferred embodiment, the isolated nucleic acid molecule has the nucleotide sequence shown SEQ ID NO:3, or a complement thereof. In another embodiment, the nucleic acid molecule further comprises nucleotides 1-54 of SEQ ID NO:1. In another embodiment, the nucleic acid molecule further comprises nucleotides 490-1512 of SEQ ID NO:1. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:1. In yet another preferred embodiment, an isolated nucleic acid molecule has the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 209886. In another preferred embodiment, the nucleic acid molecule comprises a fragment of at least 476 nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, the DNA insert of the plasmid deposited with ATCC as Accession Number 209886, or a complement thereof.
In another embodiment, an MSP-5 nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence sufficiently homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or an amino acid sequence encoded by the DNA insert of the plasmid deposited with ATCC as Accession Number 209886. In a preferred embodiment, an MSP-5 nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more homologous to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4 (e.g., the entire amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4) or the amino acid sequence encoded by the DNA insert of the plasmid deposited with ATCC as Accession Number 209886. In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of human MSP-5. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or the amino acid sequence encoded by the DNA insert of the plasmid deposited with ATCC as Accession Number 209886.
In another embodiment, an isolated nucleic acid molecule of the present invention encodes a protein, preferably an MSP-5 protein, which includes a signal peptide.
Another embodiment of the invention features nucleic acid molecules, preferably MSP-5 nucleic acid molecules, which specifically detect MSP-5 nucleic acid molecules relative to nucleic acid molecules encoding non-MSP-5 proteins. For example, in one embodiment, such a nucleic acid molecule is at least 350, 400, 450, 476, 500, 550, 600, 650, 700, 750, or 800 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 209886, or a complement thereof. In a particularly preferred embodiment, the nucleic acid molecule comprises a fragment of at least 476 nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, the DNA insert of the plasmid deposited with ATCC as Accession Number 209886, or a complement thereof. In preferred embodiments, the nucleic acid molecules are at least 15 (e.g., contiguous) nucleotides in length and hybridize under stringent conditions to nucleotides 1-46, 772-799, or 1509-1512 of SEQ ID NO:1. In other preferred embodiments, the nucleic acid molecules include nucleotides 1-46, 772-799, or 1509-1512 of SEQ ID NO:1.
In other preferred embodiments, the nucleic acid molecule encodes a naturally occurring allelic variant of a polypeptide which includes the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or an amino acid sequence encoded by the DNA ins

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