Genes and pathways differentially expressed in bipolar disorder and/or major depressive disorder

• US 20060051786A1
• Filed: 06/21/2005
• Published: 03/09/2006
• Est. Priority Date: 06/21/2004
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Evans, Simon J., Jones, Edward G., Watson, Stanley J., Thompson, Robert C., Lopez, Juan F., Myers, Richard M., Li, Jun, Tomita, Hiroaki, Akil, Huda, Vawter, Marquis P., Choudary, Prabhakara V., Schatzberg, Alan F., Bunney, William E. Jr., Molnar, Margherita, Stein, Richard, Lyons, David M.
• Granted Patent: US 8,415,298 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 Haplotypes
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2800/304 Mood disorders, e.g. bipolar, depression
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

The present invention provides methods for diagnosing mental disorders. The invention also provides methods of identifying modulators of mental disorders as well as methods of using these modulators to treat patients suffering from mental disorders.

Claims

1. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleotide sequence of Table 3-6; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for a mood disorder.

2. The method of claim 1, wherein the reagent is an antibody.

3. The method of claim 1, wherein the reagent is a nucleic acid.

4. The method of claim 1, wherein the reagent associates with a polynucleotide.

5. The method of claim 1, wherein the regent associates with a polypeptide.

6. The method of claim 1, wherein the biological sample is obtained from amniotic fluid.

7. The method of claim 1, wherein the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

8. The method of claim 1, wherein the level of reagent that associates with the sample is higher than a level associated with humans without a mood disorder.

9. The method of claim 1, wherein the level of reagent that associates with the sample is lower than a level associated with humans without a mood disorder.

48. A method for treating a subject with a mood disorder, wherein said mood disorder was diagnosed according to a method of any of claims 1, 16, 29, or 38, comprising administering a therapeutic formulation which increases the activity of an FGF gene product in said subject.

49. The method of claim 48 wherein said formulation comprises a recombinant FGF gene product.

50. The method of claim 49 wherein said FGF gene product is FGF-2.

51. The method of claim 48 wherein said formulation comprises a vector capable of expressing an FGF gene product in targeted cells of said subject.

52. The method of claim 51 wherein said FGF gene product is FGF-2.

53. The method of claim 48 wherein said mood disorder is MDD.

10. A method of identifying a compound for treatment or prevention of a mood disorder, the method comprising the steps of:

(i) contacting the compound with a polypeptide, the polypeptide encoded by a polynucleotide that hybridizes under stringent conditions to a nucleic acid sequence comprising a nucleotide sequence listed in Table 3-6 or a nucleic acid sequence of the PSPHL gene; and

(ii) determining the functional effect of the compound upon the polypeptide, thereby identifying a compound for treatment or prevention of a mood disorder.

11. The method of claim 10, wherein the contacting step is performed in vitro.

12. The method of claim 10, wherein the polypeptide is expressed in a cell and the cell is contacted with the compound.

13. The method of claim 10, the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

14. The method of claim 10, further comprising administering the compound to an animal and determining the effect on the animal.

15. The method of claim 14, wherein the determining step comprises testing the animal'"'"'s mental function.

22. A method of treating a mood disorder in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a compound identified using the method of claim 10 or claim 16.

23. The method of claim 22, wherein the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

24. The method of claim 22, wherein the compound is a small organic molecule.

16. A method of identifying a compound for treatment of a mood disorder in a subject, the method comprising the steps of:

(i) contacting the compound to a cell, the cell comprising a polynucleotide that hybridizes under stringent conditions to a nucleotide sequence listed Tables 3-10 of a nucleotide sequence of the PSPHL gene; and

(ii) selecting a compound that modulates expression of the polynucleotide, thereby identifying a compound for treatment of a mood disorder.

17. The method of claim 16, wherein the expression of the polynucleotide is enhanced.

18. The method of claim 16, wherein the expression of the polynucleotide is decreased.

19. The method of claim 16, further comprising administering the compound to an animal and determining the effect on the animal.

20. The method of claim 19, wherein the determining step comprises testing the animal'"'"'s mental function.

21. The method of claim 16, wherein the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

25. A method of treating a mood disorder in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a polypeptide, the polypeptide encoded by a polynucleotide that hybridizes under stringent conditions to a nucleotide sequence listed in Tables 3-10 or a nucleotide sequence of the PSPHL gene.

26. The method of claim 25, wherein the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

27. A method of treating a mood disorder in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a nucleic acid, wherein the nucleic acid hybridizes under stringent conditions to a nucleotide sequence listed Table 3-6 or a nucleic acid sequence of the PSPHL gene.

28. The method of claim 27, wherein the mood disorder is selected from the group consisting of bipolar disorder and major depression disorder.

29. A method for determining whether a subject has or is predisposed for bipolar disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by the PSPHL gene; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for bipolar disorder.

30. The method of claim 29, wherein the reagent is an antibody.

31. The method of claim 29, wherein the reagent is a nucleic acid.

32. The method of claim 29, wherein the reagent associates with a PSPHL polynucleotide.

33. The method of claim 29, wherein the reagent associates with a PSPHL mRNA.

34. The method of claim 29, wherein the reagent associates with a PSPHL gene.

35. The method of claim 29, wherein the regent associates with a PSPHL polypeptide.

36. The method of claim 29, wherein the biological sample is obtained from amniotic fluid.

37. The method of claim 29, wherein the level of reagent that associates with the sample is lower than a level associated with humans without bipolar disorder.

38. A method for determining whether a subject has or is predisposed for bipolar disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a PCR primer pair that selectively binds to the PSPHL gene; and

(iii) amplifying the PSPHL gene and detecting the amplified gene product in the sample, thereby determining whether the subject has or is predisposed for bipolar disorder.

39. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising:

(i) contacting the tissue of one or regions of the subject'"'"'s brain with a detectably labeled molecule that selectively binds to a gene listed in any of Tables 1-30;

(ii) visualizing the distribution of the detectably labeled molecule in the brain tissue; and

(iii) correlating the distribution of the detectably labeled molecule with the presence of or predisposition for a mood disorder in the subject.

40. The method of claim 39 wherein said one or more regions are selected from the group consisting of the anterior cingulate cortex (AnCg), dorsolateral prefrontal cortex (DLPFC), cerebellar cortex (CB), superior temporal gyrus (STG), parietal cortex (PC), and nucleus accumbens (nAcc).

41. The method of claim 39 wherein said labeled molecule is an antisense RNA molecule.

42. The method of claim 39 wherein said contacting occurs in vivo.

43. The method of claim 39 wherein said mood disorder is major depressive disorder.

44. The method of claim 39 wherein said mood disorder is bipolar disorder.

45. A method for determining the course of progression or regression of a mood disorder:

(a) measuring in a biological sample, at a first time, a dysregulated transcript associated with said mood disorder from Tables 1-30;

(b) measuring, at a second time, said dysregulated transcript in a biological sample from the subject; and

(c) comparing the first measurement and the second measurement;

wherein the comparative measurements determine the course of the mood disorder.

46. The method of claim 45 wherein said mood disorder is major depressive disorder.

47. The method of claim 45 wherein said mood disorder is bipolar disorder.

54. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleotide sequence of Table 10; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for a mood disorder.

55. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleotide sequence of Tables 18-19; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for a mood disorder.

56. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleotide sequence of Table 20; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for a mood disorder.

57. A method for determining whether a subject has or is predisposed for a mood disorder, the method comprising the steps of:

(i) obtaining a biological sample from a subject;

(ii) contacting the sample with a reagent that selectively associates with a polynucleotide or polypeptide encoded by a nucleic acid that hybridizes under stringent conditions to a nucleotide sequence of Tables 29-30; and

(iii) detecting the level of reagent that selectively associates with the sample, thereby determining whether the subject has or is predisposed for a mood disorder.

58. The method of claim 57, wherein said nucleic acid encodes a V-ATPase subunit and wherein said mood disorder is MDD or chronic stress.