Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-29
2004-03-16
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S069400, C435S007100, C435S007210, C435S007240, C435S406000, C424S198100, C424S604000
Reexamination Certificate
active
06706683
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of controlling secretion of granules from cell lines having granule secretion capability, preferably secretion of granules from neutrophils and to a method of detecting substances which inhibit or activate the granule secretion reaction based on the method of controlling secretion of granules.
BACKGROUND ART
Neutrophils play an important role in the defense of a living body. A major function of neutrophils is to migrate into bacteria and microorganisms which invade into living bodies and eat the bacteria and microorganisms, thereby rendering a sterilizing effect. In one sterilization mechanism of neutrophils, sterilization is effected after fusion of phagosomes and granules by the action of bactericidal proteins and proteases which are present in the granules. Although bactericidal proteins and proteases which are present in neutrophils are important sterilization substances, their excessive production and secretion are known to injure intima of blood vessels (Fahey, T. J. et al., In Update Pulmonary Diseases and Disorders (Fishman A P, ed) (1992) MacGraw-Hill, New York).
Intimal injury of blood vessels is deeply concerned with the occurrence of diseases such as adult respiratory distress syndrome (ARDS) (Weiland, J. E. et al., Am. Rev. Respir. Dis. (1986) 133: 218-225), injury by reperfusion after ischemia (Cavanagh, S. P. et al. Cardiovasc. Surg. (1998) 6: 112-118), glomerular nephritis (Jennette, J. C. and Falk, R. J., Am. J. Kidney Dis. (1994) 24: 130-141), cystic fibrosis (Greenberger, P. A., J. A. M. A (1997) 278: 1924-1930), rheumatoid arthritis (Chang, D. J. et al. Semin. Arthritis Rheum. (1996) 25: 390-403), chronic bronchitis (Hoidal, J. R., Semin. Respir. Infect. (1994) 9: 8-12), spasm of blood vessel (Merhi, Y. et al. Arterioscler. Thromb. (1993) 13: 951-957), asthma (Borson, D. B. et al. Am. J. Physiol. (1991) 260: L212-L225), peripheral circulation disorder and angina pectoris (Merhi, Y. et al. Arterioscler. Thromb. (1993) 13: 951-957), hypertension (Dz au, V. J., Am. J. Med. (1984) 77: 31-36), arteriosclerosis (Belch, J. J., Curr. Opin. Lipidol. (1994) 5: 440-446), and the like. Therefore, the substances which inhibit secretion of neutrophil granules are thought to be useful as a therapeutic drug for treating diseases associated with secretion of neutrophil granules. Genes which control secretion of neutrophil granules are also thought to make genetic therapy of diseases associated with secretion of neutrophil granules possible.
However, the mechanism of secretion of neutrophil granules is not yet elucidated at present. An increase in the calcium concentration in neutrophils is known to be indispensable for secretion of granules. However, no molecules which are activated by an increase in the calcium concentration and induce granule secretion are known. Therefore, there have been no specific neutrophil secretion inhibitors developed so far, nor any genetic therapy targeting the inhibition of neutrophil secretion inhibitors practiced.
The study for specifying intra neutrophil molecules which are activated by the increase in the calcium concentration and researching compounds and genes which inhibit such molecules are expected to contribute to the development of an effective preventive and/or treating agent, and curative method for diseases associated with secretion of neutrophil granules such as adult respiratory distress syndrome (ARDS), injury by reperfusion after ischemia during acute myocardial infarction, glomerular nephritis, cystic fibrosis, rheumatoid arthritis, chronic bronchitis, cerebral vasospasm, asthma, peripheral circulation disorder, angina pectoris, hypertension, arteriosclerosis, and the like.
There are three types of calgranulins: calgranulin A (Burmeister, G., Immunology (1986) 171: 461-474) (named as S100A8, MRP8, p8, or L1 light chain), calgranulin B (Burmeister, G., Immunology (1986) 171: 461-474) (named as S100A9, MRP14, 14 or L1 heavy chain), and calgranulin C (Dell' Angelica, E. C., J. Biol. Chem. (1994) 269: 28929-28936) (named as S100A12 or p6).
Calgranulin A is a calcium-binding protein with a molecular weight of about 8 kD, calgranulin B is a calcium-binding protein with a molecular weight of about 14 kD, and calgranulin C is a calcium-binding protein with a molecular weight of about 10 kD and classified in the S100 protein.
Calgranulin A and calgranulin B were cloned by E. Lagasse et al. and their whole amino acid sequences were reported in 1988 (E. Lagasse and R. G. Clerc, Molc. Cellular. Biol. (1988) No. 8, 2402-2410). Calgranulin A and calgranulin B are present specifically in neutrophils and monocytes and occupy about 5% of all proteins in neutrophils or monocytes.
As a finding suggesting intracellular physiological functions of calgranulins, the action of calgranulin A and calgranulin B inhibiting the activity of casein kinases I and II has been reported (Murao S. et al. J. Biol. Chem (1989) 264: 8356-8360).
However, physiological functions of casein kinases I and II in neutrophils and monocytes are still to be clarified. This inhibitory effect is not dependent on the calcium concentration. Therefore, the physiological function through the activity control of casein kinases I and II by calgranulin A and calgranulin B is not known at the present. As the findings suggesting extracellular physiological functions of calgranulins, the function of calgranulin A to increase migration of neutrophils and monocytes (Geczy, C. L., Biochim. Biophys. Acta (1996) 1313: 246-253) and the antibacterial activity of calgranulin A and calgranulin B (Murthy, A. R. K. et al., J. Immunol. (1993) 151: 6291-6301) have been reported.
However, the only calgranulin which exhibits neutrophil/monocyte migration activity is mouse calgranulin A. Thus, this is not a physiological activity common to other warm-blooded animals including humans. The antibacterial activity of calgranulin A and calgranulin B is due to their capability of trapping divalent metals in a solution essential for the growth of bacteria. The activity would not be a physiological function specific to calgranulins.
Only little is known about physiological functions of calgranulin A and calgranulin B at the present time. The action of calgranulin A and calgranulin B to control secretion of neutrophil or monocyte granules has not been known at all. Calgranulin C was cloned by J. D. Gottsch et al. and its whole amino acid sequence was reported in 1997 (Gottsch, J. D. et al., Trans. Am. Ophthalmol. Soc. (1997) 95: 111-125). Calgranulin C is known to be present in granulocytes, but whether calgranulin C is present in other cells is not known. Neither, is its function known. Thus, the effect of calgranulin C on the control of the mechanism of neutrophil or monocyte granule secretion has not been known.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a method of controlling secretion of granules of cell lines having granule secretion capability, and a method of detecting substances which inhibit or activate the reaction of granule secretion based on the method of controlling secretion of granules.
As a result of extensive studies to achieve the above objective, the inventors of the present invention have found that secretion of granules can be controlled in the following manner. Specifically, if a treatment to increase the amount of active form of calgranulin is carried out on a cell line having the capability of secreting granules, the cell line increases secretion of granules; and if a treatment to decrease the amount of active form of calgranulin is carried out, granule secretion from the cell line decreases. This finding has led to the completion of the present invention.
Specifically, the present invention provides a method of controlling granule secretion which comprises performing a treatment to increase or decrease an active form of calgranulin on a cell line having the capability of secreting granules.
The cell line having granule secretion capability used herein is not specifically limited inasmuc
Fukuda Kouichirou
Seto Minoru
Asahi Kasei Pharma Corporation
Carlson Karen Cochrane
Liu Samuel W.
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