Hypertension associated transcription factors and uses therefor

Details Hypertension associated transcription factors and uses therefor Hypertension associated transcription factors and uses therefor

1999-09-03

2003-02-18

Carlson, Karen Cochrane (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...

C435S320100, C435S252300, C435S325000, C536S023100, C530S300000, C530S350000

Reexamination Certificate

active

06521420

ABSTRACT:

BACKGROUND OF THE INVENTION
Hypertension is a multi-factorial, pathogenic process associated with a number of occlusive vascular diseases including myocardial infarction, stroke, and end-stage renal failure (Lifton, R. P. (1995)
Proc. Nat. Acad. Sci
. 92:8545-51). Essential (or primary) human hypertension, as opposed to the more rare monogenetic forms, appears to be controlled by genetic and epigenetic events. To date, several forms of monogenetic (Mendelian) human hypertension have been reported, where single gene defects result in a hypertensive phenotype in the vast majority of affected individuals. These include pseudoaldosteronism (Liddle syndrome, described in Shimkets, R. A. et al. (1994)
Cell
79:407-14), glucocorticoid-remediable aldosteronism (GRA, described in Lifton, et al. (1992)
Nature
. 355:262-5), and most recently apparent mineralocorticoid excess (AME, described in Mune et al. (1995)
Nat. Gen
. 10(4):394-9), and pseudohypoaldosteronism type II (Gordon syndrome, described in Gordon et al. (1995) Raven, N.Y., pp. 2111-23).
Evidence which supports the influence of heredity in essential hypertension includes epidemiologic studies, which demonstrate significant familial aggregation of blood pressure (Longini, et al. (1984)
Am. J. Epidemiol
. 120:131-44.) This is attributable to a genetic causation in that biological siblings have a higher level of blood pressure concordance than adoptive siblings raised within the same family (Biron et al. (1976)
Can. Med. Assoc. J
. 114:773-4). Additionally, identical twin studies have demonstrated a higher concordance in blood pressure than that seen in fraternal twins (Christian, J. C. (1985) Ross Laboratories, Columbus, Ohio, pp. 51-55). However, in spite of these observations a number of epigenetic factors have also been reasoned to influence development of hypertension, including age, body mass, gender, and diet (Lifton, R. P, 1995).
Investigations into the etiology and inception of human hypertension have been centered around the use of inbred animal models of genetic hypertension, which present efficient, easily manipulatable systems for molecular and genetic analyses. Rodent models of hypertension include the spontaneously hypertensive rat (SHR), the stroke-prone SHR (SP-SHR), the Dahl salt-sensitive rat, the John Rapp salt-sensitive strain of rat, and numerous mouse strains (Dzau et al. (1995)
Circulation
92(2):521-31). Advantages of using rodent models of hypertension include the genetic homogeneity achieved by fully inbred strains and the ability to produce cross-bred hybrid strains of predetermined genetic composition in suitably large populations (Hubner et al. (1995)
Herz
. 20:309-14).
The widely-used SHR has been studied in great detail. This animal model is characterized by a number of phenotypic abnormalities, including vascular and cardiac hypertrophy, and alterations in angiotensin responsiveness, which have been linked to the development and maintenance of hypertension (Yamori, Y. (1982)
Hypertension
. pp-556-81). Changes in the SHR cerebral microcirculation have also been reported (Herman, I. M. et al, (1988).
Tissue
&
Cell
. 20(1):1-12. The SHR is amenable for mapping of genes linked to hypertension due to its genetic homogeneity. To date, candidate loci include angiotensin-converting enzyme (Jacob et al. (1991)
Cell
. 67:213-24), neuropeptide Y (NYP) (Katsuya et al (1993)
Biochem. Biophys. Res. Commun
. 192:261-7), renin (Rapp et al (1989)
Science
. 243:542-4), guanylyl cyclase A/atrial natriuretic peptide receptor (GCA) (Krieger et al (1994)
Hypertension
12:(S3):S66), heat shock protein 70 (hsp70) (Hamet et al (1992)
Hypertension
19:611-4); and S
A
(Krieger et al. (1992)
Hypertension
20:412). The results of these studies confirm that like essential hypertension in humans, hypertension in rodents is a polygenic disease. This reinforces the importance of animal modeling in trying to understand human disease to determine the molecular mechanism(s) by which the onset of hypertension occurs and how the process is maintained.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel molecules which are differentially expressed in hypertensive humans, rats, and mice, referred to herein as “hypertension associated transcription factor-1” (“HATF-1”) nucleic acid and protein molecules, as well as homologues thereof, referred to herein as “HATF-1 Related Protein-1” (“HRP-1”) nucleic acid and protein molecules. The HATF-1 and HRP-1 molecules of the present invention are useful as agents for diagnosing or prognosing subjects at risk for developing a cardiovascular disorder, e.g., hypertension, as well as modulating agents in regulating a variety of cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding HATF-1 and HRP-1 proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of HATF-1-encoding and HRP-1-encoding nucleic acids.
In one embodiment, an HATF-1 and HRP-1 nucleic acid molecule of the invention is at least 50%, 55%, 60%, 65%, 70%, 73%, 75%, 80%, 85%, 86%, 87%, 89%, 90%, 95%, 98%, or more homologous to the nucleotide sequence (e.g., to the entire length of the nucleotide sequence) shown in SEQ ID NO:1, 3, or 5 or a complement thereof.
In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown SEQ ID NO:1, 3, or 5 or a complement thereof. In another preferred embodiment, the nucleic acid molecule consists of the nucleotide sequence shown in SEQ ID NO:1, 3, or 5. In another preferred embodiment, the nucleic acid molecule includes a fragment of at least 100 nucleotides of the nucleotide sequence of SEQ ID NO:1, 3, or 5 or a complement thereof.
Another embodiment of the invention features nucleic acid molecules, preferably HATF-1 and HRP-1 nucleic acid molecules, which specifically detect HATF-1 and HRP-1 nucleic acid molecules relative to nucleic acid molecules encoding non-HATF-1 and non-HRP-1 proteins, respectively. For example, in one embodiment, such a nucleic acid molecule is at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500 or more nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, 3, or 5 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 the nucleotide sequence of SEQ ID NO:1, 3, or 5 or a complement thereof.
Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to an HATF-1 or HRP-1 nucleic acid molecule, e.g., the coding strand of an HATF-1 or HRP-1 nucleic acid molecule.
Another aspect of the invention provides a vector comprising an HATF-1 or HRP-1 nucleic acid molecule. In certain embodiments, the vector is a recombinant expression vector. In another embodiment, the invention provides a host cell containing a vector of the invention.
In another aspect, the present invention provides a method for detecting the presence of an HATF-1 or HRP-1 nucleic acid molecule, protein or polypeptide in a biological sample by contacting the biological sample with an agent capable of detecting an HATF-1 or HRP-1 nucleic acid molecule, protein or polypeptide such that the presence of an HATF-1 or HRP-1 nucleic acid molecule, protein or polypeptide is detected in the biological sample.
In another aspect, the present invention provides a method for detecting the presence of HATF-1 or HRP-1 activity in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of HATF-1 or HRP-1 activity such that the presence of HATF-1 or HRP-1 activity is detected in the biological sample.
In another aspect, the invention provides a method for modulating HATF-1 or HRP-1 activity comprising contacting a cell capable of expressing

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