DNA encoding Rhesus ob protein

Details DNA encoding Rhesus ob protein DNA encoding Rhesus ob protein

1995-05-26

2002-05-28

Carlson, Karen Cochrane (Department: 1653)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S252300, C435S325000, C435S071100, C536S023500, C536S023510

Reexamination Certificate

active

06395509

ABSTRACT:

The invention belongs to the general field of molecular biology as applied to biopharmaceutical research and development. The invention includes nucleic acid compounds, vectors and methods useful for expressing proteins that help regulate the body's volume of adipose tissue.
BACKGROUND OF THE INVENTION
Obesity, especially upper body obesity, is a common and very serious public health problem in the United States and throughout the world. According to recent statistics, more than 25% of the U.S. population and 27% of the Canadian population are over weight. Kuczmarski,
Amer. J. of Clin. Nut.
55: 495S-502S (1992); Reeder et al.,
Can. Med. Ass. J,
23: 226-233 (1992). Upper body obesity carries the highest risk factor known for Type II Diabetes and is a significant risk factor for cardiovascular disease and cancer as well. Recent cost estimates for medical complications associated with obesity are $150 billion world wide. The problem has now become so serious that the Surgeon General has begun a national initiative to combat obesity in America.
Hypertension, dyslipidemia, and insulin resistance are the primary pathologies associated with obesity. Many studies have demonstrated that weight reduction through diet and exercise dramatically improves these serious medical conditions. Unfortunately, obese individuals generally fail to significantly reduce their body mass through diet and exercise and have a near 95% failure rate. This failure may be due to genetically inherited factors that contribute to increased appetite, preference for high calorie foods, reduced physical activity, reduced lipolytic metabolism, and increased lipogenic metabolism. This indicates that people inheriting these genetic traits are prone to becoming obese regardless of their efforts to combat the condition. Therefore, new pharmacological agents that can reverse obesity in spite of genetic predisposition are needed.
The ob/ob mouse model of obesity and diabetes is known to carry an autosomal recessive trait linked to a mutation in the sixth chromosome. Recently, Zhang and co-workers published the positional cloning of a mouse gene linked to this condition. Zhang et al.
Nature
372: 425-32 (1994). This report discloses a mouse cDNA sequence encoding a 167 amino acid protein that is expressed exclusively in adipose tissue and compares this mouse ob gene product to a human homolog. The report also discloses a point mutation resulting in the conversion of an Arg codon to a stop codon at position 105. This mutant gene is postulated to expresses a truncated protein that lacks the biological function of the complete intact protein.
Physiologist have long postulated that excess fat cells laid down through overeating signals the brain that the body is obese which, in turn, causes the body to eat less and burn more fuel. G. R. Hervey,
Nature
227: 629-631 (1969). Parabiotic experiments support a “feedback” model and suggest that a circulating peptide hormone may regulate the size of the body's fat depot. The newly disclosed ob gene product mentioned above is now believed to be such a hormone.
The present invention is based on the discovery of a an obesity gene cloned from Rhesus monkey adipose tissue. Therefore, this invention is useful for producing what is currently believed to be a biologically active anti-obesity protein useful for treating obesity and reducing the risk for Type II diabetes, cardiovascular diseases, and cancer in mammals.
The invention is also useful in a Rhesus immunogenicity model. In this mode, the invention can be used to predict the immunogenic capacity of analogs of the human ob gene product. For example, if one wished to determine whether a specific substitution in the human ob gene product would produce an antibody response in humans, the corresponding substitution could be made in the Rhesus ob protein. The Rhesus analog is then injected into a Rhesus monkey and its immunological response monitored. If the subtitution failed to produce an immunological response, one would then accurately predict that the corresponding substitution in the human ob protein also would not raise an immunological response in a human.
SUMMARY OF THE INVENTION
The invention is drawn to isolated nucleic acid molecules consisting of a nucleotide sequence that encodes a protein having the amino acid sequence of SEQ ID NO: 2. Recombinant DNA vectors and host cells comprising such nucleic molecules make up further embodiments of the invention. Processes for producing anti-obesity proteins comprising culturing such host cells and isolating a protein comprising the amino acid sequence of SEQ ID NO: 2 is also claimed.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of the present invention, as disclosed and claimed herein, the following terms and abbreviations are defined as follows:
Base pair (bp)—refers to DNA or RNA. The abbreviations A,C,G, and T correspond to the 5′-monophosphate forms of the nucleotides (deoxy)adenine, (deoxy)cytidine, (deoxy)guanine, and (deoxy)thymine, respectively, when they occur in DNA molecules. The abbreviations U,C,G, and T correspond to the 5′-monophosphate forms of the nucleosides uracil, cytidine, guanine, and thymine, respectively when they occur in RNA molecules. In double stranded DNA, base pair may refer to a partnership of A with T or C with G. In a DNA/RNA heteroduplex, base pair may refer to a partnership of T with U or C with G.
DNA—Deoyxribonucleic acid.
RNA—Ribonucleic acid Nucleic acid molecule—DNA or RNA.
Plasmid—an extrachromosomal self-replicating genetic element.
Reading frame—the nucleotide sequence from which translation occurs “read” in triplets by the translational apparatus of tRNA, ribosomes and associated factors, each triplet corresponding to a particular amino acid. Because each triplet is distinct and of the same length, the coding sequence must be a multiple of three. A base pair insertion or deletion (termed a frameshift mutation) may result in two different proteins being coded for by the same DNA segment. To insure against this, the triplet codons corresponding to the desired polypeptide must be aligned in multiples of three from the initiation codon, i.e. the correct “reading frame” must be maintained. In the creation of fusion proteins containing a chelating peptide, the reading frame of the DNA sequence encoding the structural protein must be maintained in the DNA sequence encoding the chelating peptide.
Recombinant DNA Cloning Vector—any autonomously replicating agent including, but not limited to, plasmids and phages, comprising a DNA molecule to which one or more additional DNA segments can or have been added.
Recombinant DNA Expression Vector—any recombinant DNA cloning vector in which a promoter has been incorporated.
Recombinant Host Cell—Any cell transformed using a recombinant DNA Vector and which is capable of either replicating or transcribing and translating DNA used to construct the recombinant DNA Vector.
Replicon—A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector.
Transcription—the process whereby information contained in a nucleotide sequence of DNA is transferred to a complementary RNA sequence.
Translation—the process whereby the genetic information of messenger RNA is used to specify and direct the synthesis of a polypeptide chain.
Treating—describes the management and care of a human or veterinary patient for the purpose of combating a disease, condition, or disorder, of the patient. Treating includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, eliminating the disease, condition, or disorder. Treating therefore includes the inhibition of food intake, the inhibition of weight gain, and inducing weight loss in patients in need thereof.
Vector—a replicon used for the transformation of cells in gene manipulation bearing polynucleotide sequences corresponding to appropriate protein molecules which, when combined with appropriate control sequences, confer speci

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