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  Identification of oligoadenylate synthetase-like genesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) DoaiThe Patent Description & Claims data below is from USPTO Patent Application 20080081780. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of to U.S. Provisional Application No. 60/381,408 filed on May 17, 2002, and claims priority to U.S. patent application Ser. No. 10/439,741, filed May 16, 2003, both of which are incorporated herein by reference in their entireties. FIELD OF INVENTION [0003] The present invention relates to the field of medicine. More particularly, it relates to pharmaceutical compositions and methods for modulating conception in animals. Yet further, the present invention relates to pharmaceutical compositions and methods for modulating diseases of the reproductive organs, such as hyperproliferative diseases. BACKGROUND [0004] Viral infection and interferons can induce the expression of 2',5'-oligoadenylate synthetases (OAS) (Rebouillat et al., 1999). These OAS proteins are expressed "ubiquitously" in humans and mice. In humans, there are three reported OAS genes (small, OAS1; medium, OAS2; and large, OAS3) and one OAS-like gene (OASL) which are linked on human chromosome 12. There are two mouse OAS genes (Oas1A and Oas1B) that arose from a gene duplication and encode "small" OAS proteins, as well as an OAS-like gene (Oasl5). OASL5 protein is 60% identical to mouse OAS1A and 1B (Shibata et al., 2001) but distinct from human OASL. The three human OAS proteins and the mouse OAS proteins, except OASL or OASL5, share the ability to convert ATP into 2',5'-linked oligomers of adenosine (2-5A) in the presence of double stranded (ds) RNA. GTP can also act as a substrate for OAS, though the in vivo significance of this is not understood. 2-5A oligomers bind and activate RNAse L leading to degradation of viral and cellular RNA and thereby downregulating protein production. However, it is not known if OAS or OAS-like proteins have RNAse L-independent antiviral activities or function in cellular processes unrelated to viral infection (i.e., degradation of oocyte mRNA species after fertilization). [0005] Thus, the inventors of the present invention have identified an OAS related family member and provide the first indication that oligoadenylate synthetase-like proteins function in gametogenesis and early embryonic development. It is envisioned that modulation of this protein play a role in contraception, fertility, cell proliferative disease, i.e., cancer, or other reproductive diseases. BRIEF SUMMARY OF THE INVENTION [0006] The present invention is drawn to a novel polynucleotide, polypeptide and variants thereof. Compositions of the present invention are involved in gametogenesis or early embryonic development. It is envisioned that the novel polynucleotide or polypeptide mediates mRNA degradation pathways important for gametogenesis or early embryonic development. Yet further, the polynucleotide or polypeptide can mediate mRNA degradation pathways that play a role in the cell proliferation. [0007] The present invention provides polynucleotide sequences SEQ. ID. NO.1, SEQ. ID. NO.3, SEQ. ID. NO.5, SEQ. ID. NO.7, SEQ. ID. NO.9, and SEQ. ID. NO.11.; the protein products they encode, fragments, homologues, and derivatives thereof, and antibodies which are immunoreactive with these protein products. [0008] In a specific embodiment, the present invention provides nucleic acid molecules. These specific nucleic acids may be a naturally-occurring cDNA, genomic DNA, RNA, or a fragment of one of these nucleic acids, or may be a non-naturally-occurring nucleic acid molecule. In preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of SEQ. ID. NO.2, SEQ. ID. NO.4, SEQ. ID. NO.6, SEQ. ID. NO.8, SEQ. ID. NO.10, or SEQ. ID. NO.12. In yet another embodiment, the nucleic acid molecule comprises a nucleic acid sequence of SEQ. ID. NO.1, SEQ. ID. NO.3, SEQ. ID. NO.5, SEQ. ID. NO.7, SEQ. ID. NO.9, and SEQ. ID. NO.11. By nucleic acid molecule, it is also meant to be inclusive of sequences that selectively hybridize or exhibit substantial sequence similarity to a nucleic acid molecule encoding a gonadal specific protein, or that selectively hybridize or exhibit substantial sequence similarity to a gonadal specific nucleic acids, as well as allelic variants of a nucleic acid molecule encoding a gonadal specific protein, and allelic variants of a gonadal specific nucleic acids. [0009] It is also contemplated that the polynucleotide sequence of the present invention may be an expression cassette comprising the polynucleotide sequence of the present invention operatively linked to a promoter sequence. Still further, the expression cassette may be comprised in a vector. [0010] Another embodiment of the present invention is a pharmaceutical composition comprising a modulator of OASL expression dispersed in a pharmaceutically acceptable carrier. The modulator suppresses and/or enhances transcription of an Oasl gene, for example Oasl6, Oasl7, Oasl8, Oasl9, Oasl10 or Oasl11. Specifically, the modulator can be a polypeptide, a small molecule, a polynucleotide sequence (e.g., is DNA or RNA), and/or an expression vector containing a polynucleotide sequence. [0011] Still further, the present invention provides a pharmaceutical composition comprising a modulator of OASL activity dispersed in a pharmaceutically acceptable carrier. The modulator is a composition that inhibits or stimulates OASL activity, for example, OASL6, OASL7, OASL8, OASL9, OASL10 and OASL11. [0012] Another embodiment is a method of identifying compounds that modulate the activity of OASL comprising the steps of: obtaining an isolated OASL polypeptide or functional equivalent thereof; admixing the OASL polypeptide or functional equivalent thereof with a candidate compound; and measuring an effect of the candidate compound on the activity of OASL. The OASL is selected from the group consisting of OASL6, OASL7, OASL8, OASL9, OASL10 and OASL11. The effect is a decrease in mRNA degradation and/or an increase in mRNA degradation. [0013] A further embodiment is a method of screening for a compound which modulates the activity of OASL comprising: exposing OASL or an OASL binding fragment thereof to a candidate compound; and determining whether the compound binds to OASL or the OASL binding fragment thereof; and further determining whether the compound modulates OASL activity or the interaction of OASL its binding partner. [0014] Still further, another embodiment is a method of screening for an interactive protein which binds with OASL protein comprising: exposing the OASL protein, or OASL fragment thereof to a candidate compound; and determining whether the compound binds to the OASL protein, wherein binding of the candidate compound to the OASL protein indicates an interactive protein. [0015] Another embodiment is a method of identifying a compound that effects OASL activity comprising the steps of: providing a transgenic animal having a regulatable one or more genes encoding an OASL protein, a knock-out of one or more genes encoding an OASL protein, or a knock-in of one or more genes encoding an OASL protein; providing a control animal for the transgenic animal and exposing the transgenic animal group and control animal group to a candidate OASL-modulating compound; and comparing the transgenic animal and the control animal and determining the effect of the compound on one or more OASL proteins related to infertility or fertility in the transgenic animals as compared to the control animals. [0016] A specific embodiment is a method of detecting a binding interaction of a first peptide and a second peptide of a peptide binding pair, comprising the steps of: culturing at least one eukaryotic cell under conditions suitable to detect the selected phenotype; wherein the cell comprises; a polynucleotide sequence encoding a first heterologous fusion protein comprising the first peptide or a segment thereof joined to a DNA binding domain of a transcriptional activation protein; a nucleotide sequence encoding a second heterologous fusion protein comprising the second peptide or a segment thereof joined to a transcriptional activation domain of a transcriptional activation protein; wherein binding of the first peptide or segment thereof and the second peptide or segment thereof reconstitutes a transcriptional activation protein; and; a reporter element activated under positive transcriptional control of the reconstituted transcriptional activation protein, wherein expression of the reporter element produces a selected phenotype; detecting the binding interaction of the peptide binding pair by determining the level of the expression of the reporter element which produces the selected phenotype; wherein said first or second peptide is an OASL peptide and the other peptide is a test peptide, preferably selected peptides/proteins present in the ovary. [0017] Another specific embodiment is a rescue screen for detecting the binding interaction of a first peptide and a second peptide of a peptide binding pair, comprising: culturing at least one eukaryotic cell under conditions to detect a selected phenotype or the absence of such phenotype, wherein the cell comprises; a nucleotide sequence encoding a first heterologous fusion protein comprising the first peptide or a segment thereof joined to a DNA binding domain of a transcriptional activation protein; a nucleotide sequence encoding a second heterologous fusion protein comprising the second peptide or a segment thereof joined to a transcriptional activation domain of a transcriptional activation protein; wherein binding of the first peptide or segment thereof and the second peptide or segment thereof reconstitutes a transcriptional activation protein; and a reporter element activated under positive transcriptional control of the reconstituted transcriptional activation protein, wherein expression of the reporter element prevents exhibition of a selected phenotype; detecting the ability of the test peptide to interact with OASL by determining whether the test peptide affects the expression of the reporter element which prevents exhibition of the selected phenotype, wherein said first or second peptide is an OASL peptide and the other peptide is a test peptide, preferably selected peptides/proteins present in the ovary. [0018] Another embodiment is a method of identifying binding partners for OASL comprising the steps of: exposing the protein to a potential binding partner; and determining if the potential binding partner binds to OASL. [0019] Still further, another embodiment is a method of screening for a modulator of OASL activity comprising the steps of: providing a cell expressing an OASL polypeptide; contacting the cell with a candidate modulator; measuring OASL expression; and comparing said OASL expression in the presence of said candidate modulator with the expression of OASL expression in the absence of said candidate modulator; wherein a difference in the expression of OASL in the presence of said candidate modulator, as compared with the expression of OASL in the absence of said candidate modulator, identifies said candidate modulator as a modulator of OASL expression. The OASL is selected from the group consisting of OASL6, OASL7, OASL8, OASL9, OASL10 and OASL11. [0020] Another embodiment is a method of producing a modulator of OASL activity comprising the steps of: providing a cell expressing an OASL polypeptide; contacting the cell with a candidate modulator; measuring OASL expression; comparing the OASL expression in the presence of the candidate modulator with the expression of OASL expression in the absence of the candidate modulator; wherein a difference in the expression of OASL in the presence of the candidate modulator, as compared with the expression of OASL in the absence of the candidate modulator, identifies the candidate modulator as a modulator of OASL expression; and producing the modulator. [0021] Still further, another method is a method of modulating mRNA degradation in a germ cell or early embryo of an animal comprising the step of administering to the animal an inhibitor of OASL activity. The germ cell is an oocyte or egg and/or spermatid or spermatazoon. The inhibitor suppresses transcription of an Oasl6, Oasl7, Oasl8, Oasl9, Oasl10 or Oasl11 gene. The inhibitor is a polypeptide or a polynucleotide sequence. The polynucleotide sequence is DNA or RNA. The RNA is an antisense Oasl RNA or is an interference RNA of Oasl RNA. [0022] Another embodiment is a method of contraception comprising administering to an animal an effective amount of a modulator of OASL activity dispersed in a pharmacologically acceptable carrier, wherein said amount is capable of decreasing conception. The OASL is selected from the group consisting of OASL6, OASL7, OASL8, OASL9, OASL10, and OASL11. The animal is female or male. Continue reading... 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