Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-03-27
2001-11-20
Ketter, James (Department: 1636)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100
Reexamination Certificate
active
06320038
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to sequencing and cloning of the 5′-flanking region of neuropeptide FF (NPFF) promoter. A neuropeptide FF (NPFF) promoter region for mouse, rat and human has been cloned and sequenced. The characterized neuropeptide FF (NPFF) promoter is useful in screening and treating for genetic diseases associated with the promoter area of the NPFF gene by modulation of activation or inhibition of NPFF gene expression through the regulatory sites in the promoter area. The promoter can also be used as a marker for its locus in the corresponding chromosome. Thus, the characterized promoter is of considerable diagnostic value and can be used in gene therapy and in DNA analyses. Further, the promoter can be used for developing genetically modified animals.
BACKGROUND OF THE INVENTION
Neuropeptide FF was originally identified as a mammalian counterpart of the molluscan cardioactive peptide FMRF-amide (Yang et al., 1985), found in the superficial dorsal horn of the spinal cord, hypothalamus, medulla and pituitary gland (Kivipelto et al. 1989). The findings that the peptide is present in the hypothalamo-pituitary system, decreases during salt-loading and is deficient in the pituitary gland of vasopressin-deficient Brattleboro rats, implicate NPFF involvement in hypothalamic regulation of pituitary functions (Majane and Yang, 1991; Majane and Yang, 1990; Majane et al., 1993). Peripherally administered NPFF raises blood pressure in rats, an effect mediated by both peripheral and central mechanisms (Allard et al., 1995; Laguzi et al., 1996). NPFF has also been implicated in sensory systems, most notably pain and morphine analgesia (Yang et al., 1985). Intracerebroventricular NPFF has been reported to induce a vigorous abstinence syndrome in morphine-tolerant rats. NPFF has attenuated the antinociceptive effects of morphine when administered in the third ventricle, whereas intrathecal NPFF produces long-lasting antinociception (Gouarderes et al., 1993).
The NPFF gene is located in the human chromosome locus 12q13 (Burke et al. 1998), which is known to be associated with a severe condition referred to as Allgrove syndrome (triple-A syndrome). The current NPFF promoter area is an evident region where mutations responsible for triple A syndrome are located. It serves as a useful marker for the appropriate area of chromosome 12, and has diagnostic and therapeutical value in treatment of a triple-A syndrome.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to clone and sequence the 5′-flanking region of the NPFF promoter in human, rat and mouse.
The promoter region cloned and characterized here plays an essential role in etiology and/or pathogenesis of CNS disorders involving NPFF, including those associated with deficient regulation of autonomic function, pain conditions, and hormonal dysfunction. Accordingly, another object of the invention is to provide potential methods of screening and treating for genetic diseases associated with the promoter area of the NPFF gene by modulation of activation or inhibition of NPFF gene expression through the regulatory sites in the promoter area. The sequence can also be used as a marker for its locus in the corresponding chromosome. Thus, the characterized promoter is of considerable diagnostic value and can be used in gene therapy and in DNA analyses.
Another object of the invention is to provide genetically modified animals.
REFERENCES:
Stephen J. Perry, A human gene encoding morphine modulating peptides related to NPFF and FMRFamide, Febs Letters vol. 409 (1997) 426-430.*
Bruce Alberts et al, Molecular Biology of The Cell Third Edition, pp. 420-421 (1994).*
Vilim et al, (Society for Neuroscience Abstracts, 1996, vol. 22, p. 1925).*
Gouardeères et al., “Antinociceptive effects of intrathecally administered F8F aminde and FMRFamide in the rat” European Journal of Pharmacology, 237, (1993), pp. 73-81.
R. Laguzzi et al., “Cardiovascular effects induced by the stimulation of neuropeptide FF receptors in the dorsal vagal comples: an autoradiographic and pharmacological study in the rat”, Brain Research 11994, pp. 1-10, (1996).
Majane et al., “Mammalian FMRF-NH2-Like Peptide in Rat Pituitary: Decrease by Osmotic Stimulus”, Peptides, vol. 12, pp. 1303-1308, 1991.
Burke et al., “Physical Mapping of the Human NPFF GEne and Investigation of its Candidacy as a Disease Gene Locus” (Abstract), Society for Neuroscience, vol. 24, 1998, p. 2046.
Okladnova et al., “A Promoter-Associated Polymorphic Repeat Modulates PAX-6 Expression in Human Brain”, Biochemical and Biophysical Research Communications, 248, pp. 402-405, 1998.
Kel et al., “Recognition of NFATp/AP-1 Composite Elements within Genes Induced upon the Activation of Immune Cells”, J. Mol. Biol., (1999), 288, pp. 353-376.
Sarge et al., “Activation of Heat Shock Gene Transcription by Heat Shock Factor 1 Involves Oligomerization, Acquisition of DNA-Binding Activity, and Nuclear Localization and Can Occur in the Absence of Stress”, Molecular and Cellular Biology, Mar. 1993, pp. 1392-1407.
Verweij et al., “Cell Type Specificity and Activation Requirements for NFAT-1 (Nuclear Factor of Activated T-cells) Transcriptional Activity Determined by a New Method Using Transgenic Mice to Assay Transcriptional Activity of an Individual Nuclear Factor”, The Journal of Biological Chemistry, vol. 265, No. 26, Issue of Sep. 15, pp. 15788-15795, 1990.
Lenardo et al., “NF-kB: Pleiotropic Mediator of Inducible and Tissue-Specific Gene Control”, Cell, vol. 58, ppl 227-229, Jul. 28, 1989.
Vilim et al., “Gene for Pain Modulatory Neuropeptide NPFF: Induction in Spinal Cord by Noxious Stimuli”, Molecular Pharmacology, 55:804-811, (1999).
Majane et al., “Origin of Neurophypophyseal Neuropeptide-FF (FLFQPQRF-NH2), ”Endocrinology, vol. 133, No. 4, pp. 1578-1584 (1993).
Yang et al., “Isolation, sequencing, synthesis, and pharmacological characterization of two brain neuropeptides that modulate the action of morphine”, Proc. Natl. Acad. Sci., vol. 82, pp. 7757-7761, 11/1985.
Kivipelto et al., “Immunohistochemical Distribution and Partial Characterization of FLFQPQRFamidelike Peptides in the Central Nervous System of Rats”, The Journal of Comparative Neurology, 286:269-287, (1989).
Allard et al., “Mechanisms Underlying the Cardiovascular Responses to Peripheral Administration of NPFF in the Rat1,2”, The Journal of Pharmacology and Experimental Therapeutics, vol. 274, No. 1, pp. 577-583, (1995).
Brandt Annika
Panula Pertti Aarre Juhani
Westerlund Johanna
Gansheroff Lisa
Ketter James
Rothwell Figg Ernst & Manbeck
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