Modulation of type ii.Beta. phosphoinositide phosphate kinase 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
CA2473990 A1 2003-08-07 [CA2473990] / 2003-08-07
申请号/申请日
2003CA-2473990 / 2003-02-03
发明人
CANTLEY LEWIS C;RAMEH LUCIA;LAMIA KATJA A;KAHN BARBARA;PERONI ODILE;
申请人
BETH ISRAEL HOSPITAL;
主分类号
IPC分类号
A01K-067/027A61K-031/155A61K-031/198A61K-031/427A61K-031/4439A61K-031/4453A61K-031/64A61K-031/7088A61K-038/00A61K-038/28A61K-045/00A61K-045/06A61K-049/00A61P-003/04A61P-003/10A61P-043/00C12N-009/12C12N-015/09C12N-015/85C12Q-001/02C12Q-
摘要
(CA2473990) The invention provides methods for modulating type II.beta. phosphoinisitide phosphate kinase (PIPKII.beta.) activity for treating PIPKII.beta.-associated disorders.  The invention also provides methods of identifying candidate agents for treating PIPKII.beta.-associated disorders.
机翻摘要
暂无翻译结果,您可以尝试点击头部的翻译按钮。
地址
代理人
代理机构
;
优先权号
2002US-60353758 2002-02-01 2003WO-US03065 2003-02-03
主权利要求
(CA2473990)  1. A method of treating a subject having or suspected of having type II diabetes comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PIPKII[beta] in the subject, as a treatment for the type II diabetes. 2. The method of claim 1, further comprising administering a pharmaceutical agent that increases sensitivity of tissues to insulin to the subject. 3. The method of claim 2, wherein the pharmaceutical agent is selected from the group consisting of: metformin, pioglitazone, and rosiglitazone. 4. The method of claim 1, further comprising administering a pharmaceutical agent that increases insulin release. 5. The method of claim 4, wherein the pharmaceutical agent is selected from the group consisting of sulfonylureas, nateglinide and repaglinide. 6. The method of claim 5, wherein the sulfonylurea is selected from the group consisting of: glibenclamide (glyburide), gliclazide and glimepiride. 7. The method of claim 1, further comprising administering insulin to the subject. 8. The method of claim 1, wherein the agent is a PIPKII[beta] inhibitor. 9. The method of claim 1, wherein the agent is an PIPKII[beta] antisense sequence. 10. A method of treating a subject having or suspected of having reduced insulin sensitivity comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PIPKII[beta] in the subject, as a treatment for the reduced insulin sensitivity. 11. The method of claim 10, further comprising administering a pharmaceutical agent that increases sensitivity of tissues to insulin to the subject. 12. The method of claim 11, wherein the pharmaceutical agent is selected from the group consisting of: metformin, pioglitazone, and rosiglitazone. 13. The method of claim 10, further comprising administering a pharmaceutical agent that increases insulin release. 14. The method of claim 13, wherein the pharmaceutical agent is selected from the group consisting of sulfonylureas, nateglinide and repaglinide. 15. The method of claim 14, wherein the sulfonylurea is selected from the group consisting of: glibenclamide (glyburide), gliclazide and glimepiride. 16. The method of claim 10, further comprising administering insulin to the subject. 17. The method of claim 10, wherein the agent is a PIPKII[beta] inhibitor. 18. The method of claim 10, wherein the agent is an PIPKII[beta] antisense sequence. 19. A method of treating a subject having or suspected of having obesity comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PIPKII[beta] in the subject, as a treatment for the obesity. 20. The method of claim 19, wherein the agent is a PIPKII[beta] inhibitor. 21. The method of claim 19, wherein the agent is an PIPKII[beta] antisense sequence. 22. A method of treating a subject having or suspected of having excess fat accumulation comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PIPKII[beta] in the subject, as a treatment for the excess fat accumulation. 23. The method of claim 22, wherein the agent is a PIPKII[beta] inhibitor. 24. The method of claim 22, wherein the agent is an PIPKII[beta] antisense sequence. 25. A method of treating a subject having or suspected of having an increased sensitivity to insulin comprising: administering to a subject in need of such treatment an agent that increases the activity of PIPKII[beta] in the subject, as a treatment for increased sensitivity to insulin. 26. A method for identifying an agent that decreases PIPKII[beta] activity, comprising: determining a first amount of activity of a PIPKII[beta] polypeptide, contacting the PIPKII[beta] polypeptide with a candidate pharmacological agent, determining the amount of activity of the contacted PIPKII[beta] polypeptide, wherein a decrease in the amount of activity of the contacted PIPKII[beta] polypeptide relative to the first amount of activity of the PIPKII[beta] polypeptide is an indication that the candidate pharmacological agent decreases PIPKII[beta] activity. 27. The method of claim 26, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 28. The method of claim 26, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO:2. 29. A method for identifying an agent that increases PIPKII[beta] activity, comprising: determining a first amount of activity of a PIPKII[beta] polypeptide, contacting the PIPKII[beta] polypeptide with a candidate pharmacological agent, determining the amount activity of the contacted PIPKII[beta] polypeptide, wherein an increase in the amount of activity in the contacted PIPKII[beta] polypeptide relative to the first amount of activity of the PIPKII[beta] polypeptide is an indication that the candidate pharmacological agent increases PIPKII[beta] activity. 30. The method of claim 29, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 31. The method of claim 29, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO:2. 32. A method of diagnosing a PIPKII[beta]-associated disorder in a subject comprising: obtaining a biological sample from a subject, determining the level of activity of a PIPKII[beta] polypeptide molecule in the biological sample, comparing the level of activity of the PIPKII[beta] polypeptide molecule in the biological sample with the level of activity of a PIPKII[beta] polypeptide molecule in a control tissue, wherein a higher level of activity of the PIPKII[beta] polypeptide molecule in the biological sample from the subject than the activity of the PIPKII[beta] polypeptide molecule in the control sample is diagnostic for a PIPKII[beta]-associated disorder in the subject. 33. The method of claim 32, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 34. The method of claim 32, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO:2. 35. The method of claim 32, wherein the biological sample is selected from the group consisting of: tissue and cells. 36. The method of claim 35, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 37. The method of claim 32, wherein the activity is determined with a kinase assay. 38. The method of claim 32, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of: diabetes and obesity. 39. A method for preparing an animal model of a disorder characterized by increased activity of a PIPKII[beta] molecule, comprising: introducing into a non-human subject a PIPKII[beta] molecule that increases PIPKII[beta] activity. 40. The method of claim 39, wherein the PIPKII[beta] molecule is a PIPKII[beta] nucleic acid molecule. 41. The method of claim 40, wherein the PIPKII[beta] nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 42. The method of claim 39, wherein the PIPKII[beta] molecule is a PIPKII[beta] polypeptide. 43. The method of claim 42, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 44. The method of claim 42, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO:2. 45. The method of claim 39, wherein the animal model is of a disorder that is selected from the group consisting o type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 46. A method for preparing an animal model of a disorder characterized by decreased expression of a PIPKII[beta] molecule, comprising: introducing into a non-human subject, a mutant PIPKII[beta] molecule, that decreases PIPKII[beta] activity. 47. The method of claim 46, wherein the PIPKII[beta] molecule is a mutant PIPKII[beta] nucleic acid molecule. 48. The method of claim 46, wherein the PIPKII[beta] molecule is a mutant PIPKII[beta] polypeptide. 49. A method for evaluating the effect of a candidate pharmacological agent on a PIPKII[beta]-associated disorder, comprising: administering a candidate pharmaceutical agent to a subject with a PIPKII[beta]-associated disorder;  determining the effect of the candidate pharmaceutical agent on the activity level of a PIPKII[beta] polypeptide relative to the activity level of a PIPKII[beta] polypeptide in a subject to which no candidate pharmaceutical agent is administered, wherein a relative increase or relative decrease in the activity level of the PIPKII[beta] polypeptide indicates an effect of the pharmaceutical agent on the PIPKII[beta]-associated disorder 50. The method of claim 49, wherein the activity level of the PIPKII[beta] polypeptide is determined with a kinase assay. 51. The method of claim 49, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO:1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 52. The method of claim 49, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO:2. 53. The method of claim 49, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 54. A method for evaluating the effect of a candidate pharmacological agent on a PIPKII[beta]-associated disorder, comprising: administering a candidate pharmaceutical agent to a subject with a PIPKII[beta]-associated disorder;  determining the effect of the candidate pharmaceutical agent on the level of expression of a PIPKII[beta] molecule relative to the level of expression of a PIPKII[beta] molecule in a subject to which no candidate pharmaceutical agent is administered, wherein a relative increase or relative decrease in the level of expression of a PIPKII[beta] molecule indicates an effect of the pharmaceutical agent on the PIPKII[beta]-associated disorder. 55. The method of claim 54, wherein the PIPKII[beta] molecule is a PIPKII[beta] nucleic acid molecule. 56. The method of claim 55, wherein the PIPKII[beta] nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 57. The method of claim 54, wherein the PIPKII[beta] molecule is a PIPKII[beta] polypeptide. 58. The method of claim 57, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 59. The method of claim 57, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 60. The method of claim 54, wherein the animal model is of a disorder that is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 61. A method of diagnosing a PIPKII[beta]-associated disorder in a subject comprising: obtaining a biological sample from a subject, determining the level of expression of a PIPKII[beta] nucleic acid molecule in the biological sample, comparing the level of expression in the biological sample with the level of expression of the nucleic acid molecule in a control biological sample, wherein a higher level of expression of the PIPKII[beta] nucleic acid molecule in the biological sample from the subject than in the control biological sample is diagnostic for a PIPKII[beta]associated disorder in the subject. 62. The method of claim 61, wherein the PIPKII[beta] nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 63. The method of claim 61, wherein the biological sample is selected from the group consisting of: tissue and cells. 64. The method of claim 63, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 65. The method of claim 61, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 66. The method of claim 61, wherein the level of expression of PIPKII[beta] nucleic acid molecules is determined by a method selected from the group consisting of nucleic acid hybridization and nucleic acid amplification. 67. The method of claim 66, wherein the nucleic acid hybridization is performed using a nucleic acid microarray. 68. The method of claim 66, wherein the nucleic acid amplification is selected from the group consisting of PCR, RT-PCR, and real-time PCR. 69. A method for determining progression or regression of a PIPKII[beta]associated disorder in a subject comprising: obtaining from a subject two biological samples, wherein the samples comprise the same tissue type and are obtained at different times, determining a level of expression of a PIPKII[beta] nucleic acid molecule in the two biological samples, and comparing the levels of expression in the two biological samples, wherein a higher level of expression of the PIPKII[beta] nucleic acid molecule in the first biological sample than in the second biological sample indicates regression of a PIPKII[beta]associated disorder, wherein a lower level of expression of the PIPKII[beta] nucleic acid molecule in the first biological sample than the second biological sample indicates progression of a PIPKII[beta]associated disorder. 70. The method of claim 69, wherein the PIPKII[beta] nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 71. The method of claim 69, wherein the biological sample is selected from the group consisting of tissue and cells. 72. The method of claim 71, wherein the tissue or cells is selected from the group consisting of skeletal muscle, brain, and adipose tissue. 73. The method of claim 69, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 74. The method of claim 69, wherein the level of expression of PIPKII[beta] nucleic acid molecules is determined by a method selected from the group consisting of nucleic acid hybridization and nucleic acid amplification. 75. The method of claim 74, wherein the nucleic acid hybridization is performed using a nucleic acid microarray. 76. The method of claim 74, wherein the nucleic acid amplification is selected from the group consisting of PCR, RT-PCR, and real-time PCR. 77. A method of diagnosing a PIPKII[beta]-associated disorder in a subject comprising: obtaining a biological sample from a subject, comparing the level of PIPKII[beta] polypeptide in the biological sample with the level of PIPKII[beta] polypeptide in a control biological sample, wherein a level of PIPKII[beta] polypeptide in the biological sample from the subject that is higher than the level of PIPKII[beta] polypeptide in the control biological sample is diagnostic for a PIPKII[beta]-associated disorder in the subject. 78. The method of claim 77, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 79. The method of claim 77, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 80. The method of claim 77, wherein the biological sample is selected from the group consisting of: tissue and cells. 81. The method of claim 80, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 82. The method of claim 77, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 83. The method of claim 77, wherein the level of expression of the PIPKII[beta] polypeptide is determined by a method selected from the group consisting of immunohistochemistry and immunoprecipitation. 84. A method for determining progression or regression of a PIPKII[beta]associated disorder in a subject comprising: obtaining from a subject two biological samples, wherein the samples comprise the same tissue type and are obtained at different times, comparing the levels of PIPKII[beta] polypeptide in the two biological samples, wherein a higher level of PIPKII[beta] polypeptide in the first biological sample than in the second biological sample indicates regression of a PIPKII[beta]-associated disorder, wherein a lower level of PIPKII[beta] polypeptide in the first biological sample than the second biological sample indicates progression of a PIPKII[beta]-associated disorder. 85. The method of claim 84, wherein the PIPKII[beta] polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:1. 86. The method of claim 84, wherein the PIPKII[beta] polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 87. The method of claim 84, wherein the biological sample is selected from the group consisting of tissue and cells. 88. The method of claim 87, wherein the tissue or cells is selected from the group consisting of skeletal muscle, brain, and adipose tissue. 89. The method of claim 84, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 90. The method of claim 84, wherein the level of expression of the PIPKII[beta] polypeptide is determined by a method selected from the group consisting of immunohistochemistry and immunoprecipitation. 91. A method of diagnosing a PIPKII[beta]-associated disorder in a subject comprising: obtaining a biological sample from a subject, determining the nucleotide sequence of a PIPKII[beta] nucleic acid molecule in the biological sample, comparing the nucleotide sequence in the subject sample with the nucleotide sequence of a control PIPKII[beta] nucleic acid molecule, wherein a difference between the nucleotide sequence in the subject biological sample and the control PIPKII[beta] nucleic acid molecule is diagnostic for a PIPKII[beta]-associated disorder in the subject. 92. The method of claim 91, wherein the PIPKII[beta] nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO: 1. 93. The method of claim 91, wherein the biological sample is selected from the group consisting of: tissue and cells. 94. The method of claim 93, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 95. The method of claim 91, wherein the PIPKII[beta]-associated disorder is selected from the group consisting of type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity.
法律状态
(CA2473990) LEGAL DETAILS FOR CA2473990  Actual or expected expiration date=2010-02-03    Legal state=DEAD    Status=LAPSED     Event publication date=2003-02-03  Event code=CA/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=CA CA2473990  Application date=2003-02-03  Standardized application number=2003CA-2473990     Event publication date=2003-08-07  Event code=CA/A1  Event type=Examination events  Application laid open  Publication country=CA  Publication number=CA2473990  Publication stage Code=A1  Publication date=2003-08-07  Standardized publication number=CA2473990     Event publication date=2008-02-01  Event code=CA/EEER  Event indicator=Pos  Event type=Examination events  Examination request    Event publication date=2010-02-03  Event code=CA/FZDE  Event indicator=Neg  Event type=Event indicating Not In Force  Dead
专利类型码
A1
国别省市代码
若您需要申请原文,请登录。

最新评论

暂无评论。

登录后可以发表评论

意见反馈
返回顶部