Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-05-14
2003-08-05
Horlick, Kenneth R. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S069100, C435S320100, C536S023100, C536S024300, C536S024310
Reexamination Certificate
active
06602667
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to eleven isolated polynucleotides and their encoded proteins that are highly co-expressed with genes known to be diagnostic markers of inflammation and useful for diagnosis, prognosis, treatment of inflammatory disorders.
BACKGROUND OF THE INVENTION
Inflammation is the body's immediate, general response to wounding or infection by a pathogen. There are many complex phenomena that occur during an inflammation response. Initiation of the complement cascade, leukocyte recruitment and leukocyte activation are three key events. In the complement cascade a set of serum proteins collectively called complement non-specifically coat foreign matter. The coating proceeds in a cascade of steps using particular subsets of factors called complement components. The coated particles are then phagocytosed by macrophages or neutrophils recruited to the inflammation site. Leukocyte recruitment of monocytes and neutrophils is mediated by cytokines, which are proteins secreted by tissue at the inflammation site. Interleukin-8 (IL-8) is the primary chemoattractant cytokine responsible for recruitment in the initial stage of inflammation. In response to IL-8, monocytes and neutrophils are activated. An immediate response to activation is the expression of L-selectin and the integrins. L-selectin is a surface molecule that facilitates leukocyte binding (with relatively low affinity) to the endothelial cells lining blood vessels in the vicinity of the inflammation site. The integrins, also cell surface molecules, have stronger binding and mediate the actual extravasation of leukoctyes from the blood vessel. Upon reaching the site of inflammation, receptors to the complement factors coating foreign particles are expressed on the leukocytes leading to phagocytosis and enzymatic degradation.
Many genes that participate in and regulate the inflammation response are known, but many remain to be identified. Identification of currently unknown genes will provide new diagnostic markers and therapeutic targets for control of the inflammation response and treatment of inflammatory disorders.
The present invention provides new compositions that are highly co-expressed with genes known to be diagnostic of inflammatory disorders and useful for diagnosis, prognosis, evaluation of therapies and treatment of inflammatory disorders.
SUMMARY OF THE INVENTION
The invention provides for a plurality of polynucleotides having the nucleic acid sequences of SEQ ID NOs:1-11 or the complements thereof that are co-expressed with genes such as CD16; L-selectin; Src-like adapter protein (SLAP); IP-30; superoxidase homoenzyme subunits, p67phox, p47phox, and p40phox; alpha-1-antitrypsin (AAT); Clq-A; 5-lipoxygenase activating protein (FLAP); and SRC family tyrosine kinase (HCK) known to be highly expressed during inflammation. The invention also provides an isolated polynucleotide comprising a nucleic acid sequence selected from SEQ ID NOs:1-or the complement thereof. In different aspects, the polynucleotide is used as a surrogate marker, as a probe, in an expression vector, and in the diagnosis, prognosis, evaluation of therapies and treatment of inflammatory disorders. The invention further provides a composition comprising either a plurality of polynucleotides or a polynucleotide and a labeling moiety.
The invention provides a method for using a composition or a polynucleotide of the invention to screen a plurality of molecules and compounds to identify ligands which bind the polynucleotide(s). The molecules are selected from DNA molecules, RNA molecules, peptide nucleic acids, peptides, mimetics, ribozymes, transcription factors, enhancers, and repressors. The invention also provides a method of using a composition or a polynucleotide to purify a ligand.
The invention provides a method for using a composition or an isolated polynucleotide to detect gene expression in a sample by hybridizing the composition or polynucleotide to nucleic acids of the sample under conditions for formation of one or more hybridization complexes and detecting hybridization complex formation, wherein complex formation indicates gene expression in the sample. In one aspect, the composition or polynucleotide is attached to a substrate. In another aspect, the nucleic acids of the sample are amplified prior to hybridization. In yet another aspect, complex formation is compared with at least one standard and indicates the presence of an inflammatory disorder.
The invention provides a purified protein or a portion thereof, SEQ ID NOs:12-17, which is encoded by a polynucleotide that is co-expressed with genes that are diagnostic markers of inflammation or inflammatory disorders. The invention also provides a method for using a protein to screen a plurality of molecules to identify at least one ligand which specifically binds the protein. The molecules are selected from aptamers, DNA molecules, RNA molecules, peptide nucleic acids, peptides, mimetics, ribozymes, proteins, antibodies, agonists, antagonists, immunoglobulins, inhibitors, pharmaceutical agents or drug compounds. The invention further provides a method of using a protein to purify a ligand.
The invention provides a method of using a protein to make an antibody that specifically binds to the protein of the invention, and methods for using the antibody to diagnose or treat an inflammatory disorder. The invention further provides a composition comprising a polynucleotide, a protein, or an antibody that specifically binds a protein and a pharmaceutical carrier.
BRIEF DESCRIPTION OF THE SEQUENCE LISTING
The Sequence Listing provides exemplary polynucleotides comprising the nucleic acid sequences of SEQ ID NOs:1-11 some of which encode the proteins comprising the amino acid sequences of SEQ ID NOs:12-17. Each sequence is identified by a sequence identification number (SEQ ID NO) and by the Incyte clone number with which the sequence was first identified.
DESCRIPTION OF THE INVENTION
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a host cell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Definitions
“Markers for inflammatory disorders” refers to polynucleotides, proteins, and antibodies which are useful in the diagnosis, prognosis, evaluation of therapies and treatment of inflammatory disorders. Typically, this means that the marker gene is differentially expressed in samples from subjects predisposed to, manifesting, or diagnosed with an inflammatory disorder.
“Differential expression” refers to an increased or upregulated or a decreased or downregulated expression as detected by presence, absence or at least about a two-fold change in the amount of transcribed messenger RNA or protein in a sample.
“Inflammatory disorders” specifically include, but are not limited to, the following conditions, diseases, and disorders: adult respiratory distress syndrome, allergy, anemia, asthma, atherosclerosis, bacterial infection, benign prostatic hyperplasia (BPH), cholecystitis, chronic heart failure (CHF), chronic ulcerative colitis, Crohn's disease, diabetes mellitus, emphysema, gastritis, hypereosinophilia, irritable bowel syndrome, lung cancer of complications thereof, lymphoma, meningitis, multiple sclerosis, osteoarthritis, psoriasis, rheumatoid arthritis, and toxic shock syndrome.
“Isolated or purified” refers to a polynucleotide or protein that is removed from its natural environment and that is separated from other components with which it is naturally present.
“Genes known to be highly expressed during inflammation” and used in the co-expression analysis included CD16; L-selectin; Src-like adapter protein (SLAP); IP-30; superoxidase homoenzyme subunits, p67phox, p47phox, and p40phox; alpha-1-antitrypsin (AAT); Clq-A; 5-lipoxygenase activating pr
Klingler Tod M.
Volkmuth Wayne
Walker Michael G.
Horlick Kenneth R.
Incyte Corporation
Incyte Corporation
Strzelecka Teresa
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