Chemistry: analytical and immunological testing – Peptide – protein or amino acid
Reexamination Certificate
2001-05-30
2004-09-14
Rao, Manjunath N. (Department: 1652)
Chemistry: analytical and immunological testing
Peptide, protein or amino acid
C435S004000, C435S006120, C435S183000, C435S069100, C435S252300, C435S320100, C536S023200, C536S023500, C536S023510
Reexamination Certificate
active
06790667
ABSTRACT:
1. INTRODUCTION
The present invention relates to the discovery, identification, and characterization of a novel human polynucleotide sequence and the novel polypeptide encoded thereby. The invention encompasses the described polynucleotides, host cell expression systems, the encoded protein or polypeptide, and fusion proteins and peptides derived therefrom, antibodies to the encoded protein or peptides, and genetically engineered animals that lack the disclosed polynucleotides, over express the disclosed polynucleotides, as well as antagonists and agonists of the protein, along with other compounds that modulate the expression or activity of the protein encoded by the disclosed polynucleotides that can be used for diagnosis, drug screening, clinical trial monitoring, the treatment of diseases and disorders, and cosmetic or nutriceutical applications.
2. BACKGROUND OF THE INVENTION
Many proteins present in the mitochondria are encoded within the nucleus. In the mitochondria, such nuclear encoded proteins are involved in, or regulate, the gradient that drives energy production in the cell/body. Accordingly, such proteins effectively modulate the efficiency of energy production in the body, and hence body metabolism. Given the role of such proteins in the body, they are thought to be important targets for the study of thermogenesis, obesity, cachexia, and other metabolically related physiological functions, diseases, and disorders.
3. SUMMARY OF THE INVENTION
The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human mitochondrial proteins that are encoded in the nucleus, and the corresponding amino acid sequences encoded by the disclosed sequences. The novel human proteins (NHPs) described for the first time herein share structural motifs typical of mammalian mitochondrial solute carriers, RNA splicing proteins, uncoupling proteins, and mitochondrial carrier proteins. The novel human nucleic acid sequence described herein encode proteins of 364, 193, 230, 265, 94, and 131 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, and 12).
An additional aspect of the present invention includes knockout cells and animals having genetically engineered mutations in gene encoding the presently described NHPs.
The invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, and the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described genes, including the specifically described NHPs and the NHP products; (b) nucleotides that encode one or more portions of a NHP that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of the described NHPs in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal sequence is deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of a NHP, or one of its domains (e.g., a transmembrane domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide.
The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPs, or portions thereof, that compete with native NHP, peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) or to enhance the expression of the described NHP polynucleotides (e.g., expression constructs that place the described polynucleotide under the control of a strong promoter system), and transgenic animals that express a NHP transgene, or “knock-outs” (which can be conditional) that do not express a functional NHP. Knock-out mice can be produced in several ways, one of which involves the use of mouse embryonic stem cells (“ES cells”) lines that contain gene trap mutations in a murine homolog of at least one of the described NHPs. When the unique NHP sequences described in SEQ ID NOS:1-12 are “knocked-out” they provide a method of identifying phenotypic expression of the particular gene as well as a method of assigning function to previously unknown genes. Additionally, the unique NHP sequences described in SEQ ID NOS:1-12 are useful for the identification of coding sequence and the mapping a unique gene to a particular chromosome.
Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.
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Hilbun Erin
Potter David George
Turner, Jr. C. Alexander
Lexicon Genetics Incorporated
Rao Manjunath N.
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