Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1993-11-24
2001-06-19
Eyler, Yvonne (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C536S023500, C435S320100, C435S242000, C435S252300, C435S254110
Reexamination Certificate
active
06248554
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of bone formation and development. Specifically, the present invention relates to a bone morphogenetic protein receptor and a DNA sequence coding for said receptor.
BACKGROUND
Humans and other warm-blooded animals can be afflicted by a number of bone-related disorders. Such disorders range from bone fractures, to debilitating diseases such as osteoporosis. While in healthy individuals, bone growth generally proceeds normally and fractures heal without the need for pharmacological intervention, in certain instances bones may become weakened or may fail to heal properly. For example, healing may proceed slowly in the elderly and in patients undergoing treatment with corticosteroids (e.g., transplant patients). Osteoporosis is a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Osteoporosis can generally be defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue; marrow and bone spaces become larger, fibrous binding decreases, and compact bone becomes fragile. Another bone related disorder is osteoarthritis, which is a disorder of the movable joints characterized by deterioration and abrasion of articular cartilage, as well as by formation of new bone at the joint surface.
While a variety of treatments are available for such bone-related disorders, none of the treatments provide optimum results. One of the difficulties facing individuals who treat bone-related disorders is a lack of complete understanding of bone metabolism and of the bone-related disorders. A key to such understanding is identifying and characterizing each of the components involved in bone growth. Bone morphogenetic proteins (BMPs) have been demonstrated to play a role in bone formation and development (Wozney, J. M.,
Molec. Reproduct. and Develop.,
32: 160-167 (1992)).
Furthermore, the role of BMPs may not be limited to their role in bone. The finding that the BMPs are found at significant concentrations in other tissues such as brain and kidney (Wall, N. A., Blessing, M., Wright, C. V. E., and Hogan, B. L. M.,
J Cell Biol.,
120: 493-502 (1993); Özkaynak, E., Schnegelsberg, P. N. J., Jin, D. F., Clifford, G. M., Warren, F. D., Drier, E. A., and Oppermann, H.,
J. Biol. Chem.,
267: 25220-25227 (1992); Lyons, K. M., Jones, C. M., and Hogan, B. L. M.,
Trends in Genetics,
7: 408-412 (1991)) suggests that they may play additional roles in development and differentiation. In support of this, BMPs have recently been found to promote nerve cell differentiation (Basler, K., Edlund, T., Jessell, T. M., and Yamada, T.,
Cell,
73: 687-702 (1993); Paralkar, V. M., Weeks, B. S., Yu, Y. M., Kleinman, H. K., and Reddi, A. H.,
J. Cell Biol.,
119: 1721-1728 (1992)).
A BMP initiates its biological effect on cells by binding to a specific BMP receptor expressed on the plasma membrane of a BMP-responsive cell. A receptor is a protein, usually spanning the cell membrane, which binds to a ligand from outside the cell, and as a result of that binding sends a signal to the inside of the cell which alters cellular function. In this case, the ligand is the protein BMP, and the signal induces the differentiation of the cell to produce cartilage and bone.
Because of the ability of a BMP receptor to specifically bind BMPs, purified BMP receptor compositions will be useful in diagnostic assays for BMPs, as well as in raising antibodies to the BMP receptor for use in diagnosis and therapy. In addition, purified BMP receptor compositions may be used directly in therapy to bind or scavenge BMPs, thereby providing a means for regulating the bone formation and development activities of BMPs. In order to study the structural and biological characteristics of BMP receptors and the role played by BMPs in the responses of various cell populations to BMPs during bone growth/formation stimulation, or to use a BMP receptor effectively in therapy, diagnosis, or assay, purified compositions of BMP receptor are needed. Such compositions, however, are obtainable in practical yields only by cloning and expressing genes encoding the receptors using recombinant DNA technology. Efforts to purify BMP receptors for use in biochemical analysis or to clone and express mammalian genes encoding BMP receptors have been impeded by lack of a suitable source of receptor protein or mRNA. Prior to the present invention, no cell lines were known to express high levels of BMP receptor constitutively and continuously, which precluded purification of the receptor for protein sequencing or construction of genetic libraries for direct expression cloning. Availability of the BMP receptor sequence will make it possible to generate cell lines with high levels of recombinant BMP receptor for biochemical analysis and use in screening experiments.
Based on the foregoing, there is a need for a BMP receptor DNA sequence and an isolated BMP receptor protein encoded by this sequence.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide an isolated BMP receptor kinase protein.
It is also an object of the present invention to provide a DNA sequence encoding a BMP receptor kinase protein.
It is also an object of the present invention to provide a recombinant expression vector encoding a BMP receptor kinase protein.
It is also an object of the present invention to provide a host cell comprising a recombinant expression vector encoding a BMP receptor kinase protein.
It is also an object of the present invention to provide a method for producing a BMP receptor kinase protein.
It is also an object of the present invention to provide a method for identifying compounds capable of binding to a BMP receptor kinase protein.
It is also an object of the present invention to provide a method for determining the amount of a compound capable of binding a BMP receptor kinase protein in a sample.
It is also an object of the present invention to provide antibodies specific for the BMP receptor protein and a method for producing them.
SUMMARY
The present invention relates to an isolated BMP receptor kinase protein or soluble fragment thereof, a DNA sequence coding for said BMP receptor kinase protein or said soluble fragment thereof, a recombinant expression vector comprising said DNA sequence, a host cell comprising said recombinant expression vector, a method of expressing said BMP receptor kinase protein or soluble fragment thereof, a method for identifying compounds capable of binding to said receptor kinase protein, a method for determining the amount of such compounds in a sample, and antibodies to the said BMP receptor kinase protein or soluble fragment thereof.
REFERENCES:
patent: 94/11502 (1994-05-01), None
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Nishida, Y., M. Hata, T. Ayaki, H. Ryo, M. Yamagata, K. Shimizu and Y. Nishizuka, “Proliferation of Both Somatic and Germ Cells is Affected in the Drosophila Mutants of Raf Proto-Oncogene”, The EMBO Journal, vol. 7, No. 3, pp. 775-781 (Mar. 1988).
Sumitomo, S., T. Saito and T. Nohno, “A New Receptor Protein Kinase From Chick Embryo Related to Type II Receptor For TGF-&bgr;”, DNA Sequence—J. DNA Sequence and Mapping, vol. 3, pp. 297-302 (1993).
ten Dijke, P., H. Ichijo, P. Franzén, P. Schulz, J. Saras, H. Toyoshima, C.Heldin and K. Miyazono, “Activin Receptor-like Kinases: A Novel Subclass of Cell-surface Receptors with Predicted Serine/Threonine Kinase Activity”, Oncogene, vol. 8, pp. 2879-2887 (Oct. 1993)
Cook Jonathan Shaun
Correa Paul Elliott
Rosenbaum Jan Susan
Ting Jerry
Andres Janet
Bott Cynthia M.
Clark Karen F.
Corstanje Bram J.
Eyler Yvonne
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