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WOA1 - Nucleic acids, proteins, and antibodies - Google Patents

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Monoclonal antibodies raised against such receptors may prove useful as therapeutics in anti-tumor, diagnostic, or other capacities. Furthermore, receptors described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states. Furthermore, the identification of new 7TM polynucleotides and polypeptides permits the development of a range of derivatives, agonists and antagonists at the nucleic acid and protein levels which in turn have applications in the treatment and diagnosis of a range of conditions such as, as non- limiting examples, infections, neural disorders, cancers, blood and skeletal system disorders, and pain, amongst many other conditions.

Summary of the Invention [12] The present invention relates to novel proteins. Zcontig sequences contig identifier Contig ID: X and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column provides the gene number in the application for each clone identifier.

The third column provides a unique contig identifier, "Contig ID: X", for each of the contig sequences disclosed in Table 1A. This method returns a measure of the probability that a given residue is found on the surface of the protein.

Regions where the antigenic index score is greater than 0. In particular embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. For those identifier codes in which the first two letters are not "AR", the second number in column 8 following the colonrepresents the number of times a sequence corresponding to the reference polynucleotide sequence e.

Probe synthesis was performed in the presence of 33P dCTP, using oligo dT to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove nonspecific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence PSL which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array.

A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]: Z", for a cDNA clone related to each contig sequence. X", for each contig sequence. A" for the BAC clone referenced in the corresponding row of the table.

B" for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location i. B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention e. The second column provides the unique contig identifier, "Contig ID: X", for the contig polynucleotide sequence.

Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database herein referred to as "NR"or a database of protein families herein referred to as "PFAM" as further described below. In specific embodiments polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by a polynucleotide in SEQ ID NO: X as delineated in columns 8 and 9, or fragments or variants thereof.

X", for contig sequences disclosed in Table 1 A. The third column provides the unique contig identifier, "Contig ID: X, the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequence s having the accession number s disclosed in the sixth column of this Table including for example, published sequence in connection with a particular BAC clone.

In further embodiments, preferably excluded from the invention are the specific polynucleotide sequence s contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table including for example, the actual sequence contained in an identified BAC clone.

Columns provide a description of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word "disease". The use of the word "disease" in column 6 is non-limiting. The tissue or cell source may be specific e. Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 9, as determined using the Morbid Map database.

Definitions [22] The following definitions are provided to facilitate understanding of certain terms used throughout this specification. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide.

B as defined in column 6 of Table IB or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.

Moreover, as used herein, a "polypeptide" refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA.

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X" was often generated by overlapping sequences contained in multiple clones contig analysis. X is deposited at Human Genome Sciences, Inc. HGS in a catalogued and archived library. Table 7 provides a list of the deposited cDNA libraries.

Z to determine the library source by reference to Tables 6 and 7. Library names contain four characters, for example, "HTWE. X, one can use Tables 1, 6 and 7 to determine the corresponding Clone ID, which library it came from and which ATCC deposit the library is contained in.

Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.

In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron.

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In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene i. In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene s.

X, or the complement thereof e. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration lower percentages of formamide result in lowered stringency ; salt conditions, or temperature.

In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations e. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions.

A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. A variety of modifications can be made to DNA and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms. When the colon is involved, an excess of mucus is often observed in the stools.

Occasionally the irritable bowel syndrome may be due to an allergy to a particular foodstuff. The syndrome may develop following an infection such as bacillary dysentery, after which the small intestine remains irritable for many months.

Defects in transport occur either because the absorptive cells ofthe intestine lack certain enzymes, whether by birth defect or by acquired disease, or because they are hindered in their work by other disease processes that infiltrate the tissues, disturb motility, permit bacteria to overpopulate the bowel, or block the pathways over which transport normally proceeds. A malabsorption disorder of unknown cause, tropical sprue, is associated with partial atrophy of the mucosa of the small intestine.

Disorders of the small intestine also include bacterial and parasitic infections. Chronic inflammations of the small intestine include tuberculosis and regional enteritis Crohn's disease. Celiac disease causes damage to the mucosa of the small intestine, though it is not clear whether it is caused by an immune reaction, or an inability to break down a toxic protein, gluten, to smaller peptide fractions.

Studies ofthe immune function of those with celiac disease suggest that at least a major part of the process is a delayed hypersensitivity reaction and that the morphological changes are correlated with the presence of circulating antibodies to gluten.

The mucosal reaction results in progressive atrophy, with dwarfing, if not complete disappearance, ofthe microvilli and villi that line the intestinal tract. Disorders ofthe Large Intestine [19] A wide variety of diseases and disorders occur in the large intestine.

A disease that is analogous to achalasia of the esophagus is an idiopathic condition called aganglionic megacolon, or Hirschsprung's disease. It is characterized by the absence of ganglion cells and normal nerve fibres from the distal or lower portion of the large intestine, which results in reduced neuromuscular transmission and ceased peristalsis. The entire colon slowly becomes more and more distended and thick-walled.

Abscesses in the perianal area are common complicating features of many diseases and disorders of the large intestine. Fungal and bacterial infections are also common causes of large intestine disorders. It varies from a mild inflammation of the mucosa of the rectum, giving rise to excessive mucus and some spotting of blood in the stools, to a severe, sudden, intense illness, with destruction of a large part ofthe colonic mucosa, considerable blood loss, toxemia and, less commonly, perforation.

The most common variety affects only the rectum and sigmoid colon and is characterized by diarrhea and the passage of mucus. Apart from the greater tendency for fistulas to form and for the wall of the intestine to thicken until the channel is obstructed, Crohn's disease is distinguishable from ulcerative colitis by microscopic findings.

In Crohn's disease, the maximum damage occurs beneath the mucosa, and lymphoid conglomerations, known as granulomata, are formed in the submucosa.

Crohn's disease attacks the perianal tissues more often than does ulcerative colitis. Although these two diseases are not common they are disabling. A peculiar form of polyp is the villous adenoma, often a slowly growing, fernlike structure that spreads along the surface of the colon for some distance. Cancers compress the colonic lumen to produce obstruction, they attach to neighbouring structures to produce pain, and they perforate to give rise to peritonitis. Cancers also may metastasize to distant organs before local symptoms appear.

These disorders usually take the form of fissures cuts or cracks in the skin or mucous membrane at the junction of the anal mucous membrane with the skin between the thighs. Anal fistulas sometimes occur as complications of serious bowel disease, as in tuberculosis or Crohn's disease ofthe bowel, or in certain parasitic diseases. A more general disorder is the enlargement of veins of the rectum and anus to form external or internal hemorrhoids. Hemorrhoids protrude, are associated with anal itching and pain, and bleed, especially when they come in contact with hard stools.

Disorders ofthe Liver [23] A variety of agents, including viruses, drugs, environmental pollutants, genetic disorders, and systemic diseases, can affect the liver. The resulting disorders usually affect one ofthe three functional components ofthe liver: Most acute liver diseases are self-limited, and liver functioning returns to normal once the causes are removed or eliminated.

In some cases, however, the acute disease process destroys massive areas of liver tissue in a short time, leading to extensive death necrosis of hepatic cells and often to death of the patient. Hepatitis may result from viral infections or toxic damage from drugs or poisons. When acute hepatitis lasts for six months or more, a slow but progressive destruction ofthe surrounding liver cells and bile ducts occurs, a stage called chronic active hepatitis.

If hepatocellular damage is severe enough to destroy entire acini clusters of lobulesthey are often replaced with fibrous scar tissue. Bile canaliculi and hepatocytes regenerate in an irregular fashion adjacent to the scar tissue and result in a chronic condition called cirrhosis of the liver.

Where inflammatory activity continues after the onset of cirrhosis, the disorderly regeneration of hepatocytes and cholangioles may lead to the development of hepatocellular or cholangiolar cancer. Such agents are believed to cause hepatitis when the formation of their toxic intermediate metabolites in the liver cell phase I reactions is beyond the capacity of the hepatocyte to conjugate, or join them with another substance for detoxification phase II reactions and excretion.

Acute canalicular cholestatic hepatitis is most commonly caused by certain drugs, such as chlorpromazine, that lead to idiosyncratic reactions or, at times, by hepatitis viruses.

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Acute congestive liver disease usually results from the sudden engorgement ofthe liver by fluids after congestive heart failure. Granulomatous hepatitis, a condition in which localized areas of inflammation granulomas appear in any portion of the liver lobule, is a type of inflammatory disorder associated with many systemic diseases, including tuberculosis, sarcoidosis, schistosomiasis, and certain drug reactions.

Granulomatous hepatitis rarely leads to serious interference with hepatic function, although it is often chronic. The end result of many forms of chronic liver injury is cirrhosis, or scarring of liver tissue in reponse to previous acinar necrosis and irregular regeneration of liver nodules and bile ducts.

Secondary biliary cirrhosis results from chronic obstruction or recurrent infection in the extrahepatic bile ducts caused by strictures, gallstones, or tumors.

WOA2 - Nucleic acids, proteins, and antibodies - Google Patents

Infestation of the biliary tract with a liver fluke, Clonorchis sinensis, is a cause of secondary biliary cirrhosis in Asia. The increased pressure causes feeders ofthe portal vein to distend markedly, producing varices, or dilations of the veins.

When varices are located in superficial tissues, they may rupture and bleed profusely. Two such locations are the lower esophagus and the perianal region. The accumulation of fluid in the abdominal cavity, or ascites, is related to portal hypertension, significant reduction in serum albumin, and renal retention of sodium.

When albumin levels in blood are lower than normal, there is a marked reduction in the force that holds plasma water within the blood vessels and normally resists the effects ofthe intravascular pressure. The resulting increase in intravascular pressure, coupled with the increased internal pressure caused by the portal venous obstruction in the liver, leads to massive losses of plasma water into the abdominal cavity. The associated reduction of blood flow to the kidneys causes increased elaboration of the hormone aldosterone, which, in turn, causes the retention of sodium and water and a reduction in urinary output.

In addition, because the movement of intestinal lymph into the liver is blocked by the cirrhotic process in the liver, the backflow of this fluid into the abdominal cavity is greatly increased. A progressive reduction in kidney function that often occurs in persons with advanced acute or chronic liver disease, hepatorenal syndrome, probably results from an inadequate perfusion of blood through the cortical outer portions of the kidneys, where most removal of waste products occurs.

With advanced hepatocytic dysfunction, a spasm of blood vessels in the renal cortex can occur, often with good blood flow to the rest of the kidney. This spasm results in progressive failure in kidney function and often leads to death. Long exposure to certain environmental poisons, such as vinyl chloride or carbon tetrachloride, has also been shown to lead to hepatic cancer.

Cancers arising elsewhere in the body, particularly in abdominal organs, lungs, and lymphoid tissue, commonly lead to metastatic cancer in the liver and are by far the most frequent type of hepatic malignancy.

Various benign types of tumors and cysts arise from certain components of the liver, such as the hepatocytes adenomas or blood vessels hemangiomas. While the cause of these lesions is not always clear, hepatic adenomas are associated with the prolonged use of female sex hormones estrogens.

Benign cysts in the liver may occur as congenital defects or as the result of infections from infestation of the dog tapeworm Echinococcus granulosus. Abscesses on the liver result from the spread of infection from the biliary tract or from other parts ofthe body, especially the appendix and the pelvic organs. Specific liver abscesses also result from infections with the intestinal parasite Entamoeba histolytica.

Disorders ofthe Biliary Tract [30] Cholelithiasis, or the formation of gallstones in the gallbladder, is the most common disease of the biliary tract. There are three types of Gallstones: Pigment stones are the result of an increased amount of bilirubin in the liver due to hemolytic disease and the consequent secretion into the biliary tract of increased amounts ofthe water-soluble conjugate, bilirubin diglucuronide, a pigment that is normally secreted in the urine.

Cholesterol and mixed cholesterol-bilirubinate stones occur when the proportion of cholesterol in bile exceeds the capacity of bile acids and lecithin to contain the total amount of cholesterol in micellar colloidal solution.

Postcholecystectomy syndrome comprises painful attacks, often resembling preoperative symptoms, that occasionally occur following the surgical removal of gallstones and the gallbladder.

These attacks may be related to intermittent muscular spasms of the sphincter of Oddi or of the bile ducts. In cancer of the bile duct, congenital cysts and parasitic infections, such as liver flukes, seem to lead to increased risks.

Persons with extensive chronic ulcerative colitis also show a greater than normal incidence of bile duct carcinoma. This condition is evident in three different types of disorders including, unconjugated, or hemolytic, jaundice; hepatocellular jaundice; and cholestatic, or obstructive jaundice. Unconjugated jaundice results when the amount of bilirubin produced from hemoglobin by the destruction of red blood cells or muscle tissue myoglobin overwhelms the normal capacity of the liver to transport it or when the ability of the liver to conjugate normal amounts of bilirubin into bilirubin diglucuronide is significantly reduced by inadequate intracellular transport or enzyme systems.

Hepatocellular jaundice arises when liver cells are damaged so severely that their ability to transport bilirubin diglucuronide into the biliary system is reduced, allowing some of this yellow pigment to regurgitate into the bloodstream.

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Cholestatic jaundice, occurs when essentially normal liver cells are unable to transport bilirubin either through the hepatocytic-bile capillary membrane, because of damage in that area, or through the biliary tract, because of anatomical obstructions e. Disorders ofthe Pancreas [33] Inflammation of the pancreas, or pancreatitis, is probably the most common disease of this organ. The disorder may be confined to either singular or repeated acute episodes, or it may become a chronic disease.

There are many factors associated with the onset of pancreatitis, including direct injury, certain drugs, viral infections, heredity, hyperlipidemia increased levels of blood fatsand congenital derangements of the ductal system. Localized, severe abdominal and midback pain resulting from enzyme leakage, tissue damage, and nerve irritation is the most common symptom of acute pancreatitis. In severe cases, respiratory failure, shock, and even death may occur.

Chronic pancreatitis rarely follows repeated acute attacks. It seems instead to be a separate disorder that results in mucus plugs and precipitation of calcium salts in the smaller pancreatic ducts. Mucous production and plugging ofthe pancreas in Cystic fibrosis patients almost invariably causes destruction and scarring of the acinar tissue, usually without damaging the islets of Langerhans. A similar process in the hepatic biliary system produces foci of fibrosis and bile duct proliferation, a singular form of cirrhosis.

Summary ofthe Invention [36] The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding iiovel polypeptides. Zcontig sequences contig identifier Contig ID: X and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.

The first column provides the gene number in the application for each clone identifier. The third column provides a unique contig identifier, "Contig ID: X", for each of the contig sequences disclosed in Table IA. This method returns a measure of the probability that a given residue is found on the surface ofthe protein.

Regions where the antigenic index score is greater than 0. In particular embodiments, polypeptides ofthe invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table IA. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.

For those identifier codes in which the first two letters are not "AR", the second. Probe synthesis was performed in the presence of 33P dCTP, using oligo dT to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence PSL which reflects the level of phosphor signal generated from the probe hybridized to each ofthe gene targets represented on the array.

A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]: Z", for a cDNA clone related to each contig sequence.