Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-04-12
2003-02-11
Huff, Sheela (Department: 1636)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387300, C530S388100, C530S389100
Reexamination Certificate
active
06518402
ABSTRACT:
TABLE OF CONTENTS
1. INTRODUCTION
2. BACKGROUND OF THE INVENTION
3. SUMMARY OF THE INVENTION
4. DESCRIPTION OF THE FIGURES
5. DETAILED DESCRIPTION OF THE INVENTION
5.1. Identification of Differentially Expressed and Pathway Genes
5.1.1. Methods for the Identification of Differentially Expressed Genes
5.1.1.1. Paradigms for the Identification of Differentially Expressed Genes
5.1.1.2. analysis of Paradigm Material
5.1.2. Methods for the Identification of Pathway Genes
5.1.3. Characterization of Differentially Expressed and Pathway Genes
5.2. Differentially Expressed and Pathway Genes
5.2.1. Differentially Expressed Gene Sequences
5.2.2. Differentially Expressed and Pathway Gene Products
5.2.3. Antibodies Specific for Differentially Expressed or Pathway Gene Products
5.2.4. Cell- and Animal-based Model Systems
5.2.4.1. Animal-based Systems
5.2.4.2. Cell-based Assays
5.3. Screening Assays for Compounds that Interact with the Target Gene Product
5.3.1. In Vitro Screening Assays for Compounds that Bind to the Target Gene Product
5.3.2. Assays for Cellular Proteins that Interact with the Target Gene Protein
5.3.3. Assays for Compounds that Interfere with Target Gene Product/Cellular Macromolecule Interaction
5.3.4. Assays for Amelioration of Body Weight Disorder Symptoms
5.4. Compounds and Methods for Treatment of Body Weight Disorders
5.4.1. Compounds that Inhibit Expression, Synthesis or Activity of Mutant Target Gene Activity
5.4.1.1. Inhibitory Antisense, Ribozyme and Triple Helix Approaches
5.4.1.2. Antibodies for Target Gene Products
5.4.2. Methods for Restoring Target Gene Activity
5.6. Pharmaceutical Preparations and Methods of Administration
5.6.1. Effective Dose
5.6.2. Formulations and Use
5.7. Diagnosis of Body Weight Disorder Abnormalities
5.7.1. Detection of Fingerprint Gene Nucleic Acids
5.7.2. Detection of Target Gene Peptides
6. EXAMPLE: Identification and Characterization of an Obesity-Related Gene
6.1. Materials and Methods
6.2. Results
7. EXAMPLE: Identification of Genes Differentially Expressed in Response to Short Term Appetite Control Paradigms
7.1. Materials and Methods
7.2. Results
8. EXAMPLE: Identification of Genes Differentially Expressed in Response to Genetic Obesity Paradigms
8.1. Materials and Methods
8.2. Results
9. EXAMPLE: Identification of Genes Differentially Expressed in Response to Set Point Paradigms
9.1. Materials and Methods
9.2. Results
10. EXAMPLE: Isolation and Characterization of A c5 Human Homolog
10.1. Materials and Methods
10.2. Results
11. Deposit of Microorganisms
1. INTRODUCTION
The present invention relates to methods and compositions for the modulation of processes related to mammalian body weight regulation, including treatment of body weight disorders such as obesity and cachexia, and modulation of thermogenesis. Specifically, the present invention identifies and describes genes which are differentially expressed in body weight disorder states, relative to their expression in normal, or non-body weight disorder states, and also identifies genes which are differentially expressed in response to manipulations relevant to appetite and/or weight regulation. Further, the present invention identifies and describes genes via the ability of their gene products to interact with gene products involved in body weight disorders and/or to interact with gene products which are relevant to appetite and/or body weight regulation. Still further, the present invention provides methods for the identification and therapeutic use of compounds as treatments of body weight-related processes, including body weight disorders such as obesity and cachexia. Additionally, the present invention describes methods for the diagnostic evaluation and prognosis of various body weight disorders, and for the identification of subjects exhibiting a predisposition to such conditions.
2. BACKGROUND OF THE INVENTION
The regulation of body fat in mammals is a complex process involving the regulation of not only appetite but also energy expenditure. An important component of energy expenditure is non-shivering thermogenesis (NST). In rodents, the majority of NST appears to occur in brown adipose tissue (BAT) via the uncoupling protein (UCP) (Cannon & Nedergaard, 1985, Essays in Biochem. 20:110-165; Himms-Hagen J., 1989, Prog. Lipid Res. 28:67-115). UCP is a proton channel located exclusively in the inner mitochondrial membrane of adipocytes of the BAT (Nicholls & Locke, 1984, Physiol. Rev. 64:1-64). By allowing protons to equilibrate across the inner mitochondrial membrane, UCP uncouples oxidative phosphorylation from ATP production and thus converts stored energy into heat rather than work (Klingenberg M., 1990, Trends Biochem. Sci. 15:108-112; Klaus S. et al., 1991, Int. J. Biochem. 23:791-801). UCP-mediated uncoupling is not only capable of increasing body temperature in cold-acclimatized rodents and hibernating animals, but can also dissipate surplus caloric energy (Rothwell & Stock, 1986, In
Brown Adipose Tissue
. Trayhurn P., Nicholls D. G., Eds., London, Arnold, p. 269-298; Spiegelman & Flier, 1996, Cell 87:377-38.9; Hamann & Flier, 1996, Endocrinology 137:2129). A number of studies have now implicated UCP and brown adipose tissue as important regulators of body weight in rodents (Hamann & Flier, 1996, Endocrinology 137:2129; Lowell B. B. et al., 1993, Nature 366:740-742; Kopecky J. et al., 1995, J. Clin. Invest. 96:2914-2923; Cummings D. E. et al., 1996, Nature 382:622-626).
In humans, body weight homeostasis is poorly understood, but is also thought to involve regulated thermogenesis (Rothwell & Stock, 1981, Annu. Rev. Nutr. 1:235-56; Segal K. R. et al., 1992, J. Clin. Invest. 89:824-833; Jensen M. D. et al., 1995, Am. J. Physiol. 268:E433-438). However, the importance of the UCP in adult humans is questionable due to the low levels of BAT and consequently the low levels of UCP expression (Huttunen P. et al., 1981, Eur. J. Appl. Physiol. 46:339-345; Cunningham S. et al., 1985, Clin. Sci. 69:343-348; Schulz L., 1987, J. Am. Diet Assoc. 87:761-764; Santos G.C. et al., 1992, Arch. Pathol. Lab Med. 116:1152-1154).
In adult humans and other animals that do not contain large amounts of BAT, a large portion of NST and regulated thermogenesis is thought to be mediated by muscle and the white adipose tissue (Jensen M. D. et al., 1995, Am. J. Physiol. 268:E433-438; Davis T. R. A., 1963, Am. J. Physiol. 213:1423-1426; Astrup A. et al., 1989, Am. J. Physiol. 257:E340-E345, 1989; Simonsen L. et al., 1992, Am. J. Physiol. 263:E850-E855; Simonsen J. et al., 1993, Int. J. Obes. Relat. Metab. Disord. 17 (Suppl. 3):S47-51; Duchamp C. et al., 1993, Am. J. Physiol. 265:R1076-1083), however, the molecular mediators for regulated thermogenesis are currently unknown (Block B A., 1994, Annu. Rev. Physiol. 56:535-577).
Further, body weight disorders, including eating and other disorders affecting regulation of body fat, represent major health problems in all industrialized countries. Obesity, the most prevalent of eating disorders, for example, is the most important nutritional disorder in the western world, with estimates of its prevalence ranging from 30% to 50% within the middle-aged population. Other body weight disorders, such as anorexia nervosa and bulimia nervosa which together affect approximately 0.2% of the female population of the western world, also pose serious health threats. Further, such disorders as anorexia and cachexia (wasting) are also prominent features of other diseases such as cancer, cystic fibrosis, and AIDS.
Obesity, defined as an excess of body fat relative to lean body mass, also contributes to other diseases. For example, this disorder is responsible for increased incidences of diseases such as coronary artery disease, stroke, and diabetes. Obesity is not merely a behavioral problem, i.e., the result of voluntary hyperphagia. Rather, the differential body composition observed between obese and normal subjects results from differences in both metabolism and neurologic/metabolic interactions. These differences seem to be, to some extent, due to differences
Helms Larry R.
Huff Sheela
Millennium Pharmaceuticals Inc.
Millennium Pharmaceuticals Inc.
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