Modulation of XBP-1 activity for treatment of metabolic disorders

• US 20060063187A1
• Filed: 09/15/2005
• Published: 03/23/2006
• Est. Priority Date: 09/15/2004
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Glimcher, Laurie H., Hotamisligil, Gokhan S., Ozcan, Umut
• Application Number:
  US11/227,543
• Publication Number:
  US 20060063187A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/6872 Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

The invention provides methods and compositions for modulating the expression, processing, post-translational modification, stability and/or activity of XBP-1 protein, or a protein in a signal transduction pathway involving XBP-1 to treat metabolic disorders, e.g., type II diabetes. The present invention also pertains to methods for identifying compounds that modulate the expression, processing, post-translational modification, and/or activity of XBP-1 protein or a molecule in a signal transduction pathway involving XBP-1.

Claims

1. A method of identifying a compound useful in treating at least one symptom of a metabolic disorder comprising:

a) providing an indicator composition comprising mammalian XBP-1;

b) contacting the indicator composition with each member of a library of test compounds;

c) selecting from the library of test compounds a compound of interest that increases the expression, activity, and/or stability of spliced XBP-1

to thereby identify a compound useful in treating at least one symptom of a metabolic disorder.

2. The method of claim 1, wherein the activity of XBP-1 is measured by measuring the phosphorylation of PERK or eIF2α

.

3. The method of claim 1, wherein the indicator composition comprises an indicator gene whose expression is regulated by XBP-1 and the activity of XBP-1 is measured by measuring the expression or activity of the indicator gene.

4. The method of claim 3, wherein the indicator gene is a chaperone gene.

5. The method of claim 4, wherein the chaperone gene is selected from the group consisting of:

ERdj4, p58^ipk, EDEM, PDI-P5, RAMP4, HEDJ, BiP, ATF6α

, XBP-1, Armet and DNAJB9.

6. The method of claim 3, wherein the indicator gene comprises the regulatory region of XBP-1 operably linked to nucleotide sequence encoding a measurable polypeptide and expression or activity of the polypeptide is measured.

7. The method of claim 6, wherein the measurable polypeptide is a reporter polypeptide.

8. The method of claim 1, wherein the metabolic disorder is obesity

9. The method of claim 1, wherein the metabolic disorder is insulin resistance

10. The method of claim 1, wherein the metabolic disorder is type 2 diabetes

11. A method of increasing insulin sensitivity in a cell comprising contacting a cell with an agent that increases the expression or activity of spliced XBP-1 in the cell such that insulin sensitivity is increased.

13. The method of claim 11 or 12, wherein the agent is selected from the group consisting of:

nucleic acid molecules encoding a biologically active portion of XBP-1, biologically active portions of XBP-1, and expression vectors encoding XBP-i that allow for increased expression of XBP-1 activity in a cell, and chemical compounds that act to specifically increase the activity of XBP-1.

12. A method of upmodulating glucose metabolism in a mammalian cell comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell such that glucose metabolism is decreased.

14. A method for treating at least one symptom of a metabolic disorder in a subject comprising upmodulating the expression, processing, post-translational modification, and/or activity of spliced XBP-1 to thereby treat at least one symptom of a metabolic disorder.

15. The method of claim 14, wherein the metabolic disorder is obesity

16. The method of claim 14, wherein the metabolic disorder is insulin resistance

17. The method of claim 14, wherein the metabolic disorder is type 2 diabetes

18. The method of claim 14, wherein the agent is selected from the group consisting of:

nucleic acid molecules encoding a biologically active portion of XBP-1, biologically active portions of XBP-1, and expression vectors encoding XBP-1 that allow for increased expression of XBP-1 activity in a cell, and chemical compounds that act to specifically increase the activity of XBP-1.

19. A method for diagnosing a subject at risk for developing a metabolic disorder comprising measuring the level expression of spliced XBP-1, wherein a decrease in the level of expression of spliced form of XBP-1 relative to a control indicates that the subject is at risk of developing a metabolic disorder.

21. The method of claim 19 or 20, wherein the metabolic disorder is obesity

22. The method of claim 19 or 20, wherein the metabolic disorder is insulin resistance

23. The method of claim 19 or 20, wherein the metabolic disorder is type 2 diabetes

20. A method for diagnosing a subject at risk for developing a metabolic disorder comprising measuring the level expression of a gene whose expression is upregulated by spliced XBP-1, wherein a decrease in the level of expression of the gene relative to a control indicates that the subject is at risk of developing a metabolic disorder.

24. The method of claim 20, wherein the gene is selected from the group consisting of:

ERdj4, p58^ipk, EDEM, PDI-P5, RAMP4, HEDJ, BiP, ATF6cc, XBP-1, Armet and DNAJB9.