US2002142939A1PendingUtilityA1

HMGI proteins in cancer and obesity

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Assignee: UNIV NEW JERSEY MEDPriority: Jul 12, 1996Filed: Sep 12, 2001Published: Oct 3, 2002
Est. expiryJul 12, 2016(expired)· nominal 20-yr term from priority
Inventors:Kiran K. ChadaHena AsharAlex TkachenkoXianjin Zhou
G01N 33/5758G01N 33/575C12Q 1/6883G01N 2333/4703C12Q 2600/112C07K 14/4702A61K 38/1709C12Q 1/6886C12Q 2600/106A01K 2217/05
44
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Claims

Abstract

The present invention pertains to a method for detecting HMGI-C or HMGI(Y) as a diagnostic marker for benign or malignant tumors using a probe for a sample from a patient that recognizes HMGI-C or HMGI(Y). The method comprises the steps of (a) contacting HMGI-C or HMGI(Y) from a sample from a patient with a probe which binds to HMGI-C or HMGI(Y); and (b) analyzing for HMGI-C or HMGI(Y) by detecting levels of the probe bound to the HMGI-C or HMGI(Y). The presence of HMGI-C or HMGI(Y) in the sample is positive for a benign or malignant tumor. The present invention also pertains to a method for detecting antibodies to HMGI-C or HMGI(Y) as a diagnostic marker for benign or malignant tumors. The present invention further pertains to a method for treating benign and malignant tumors in a patient by blocking the biological activity of HMGI-C or HMGI(Y). The present invention still further pertains to a transgenic non-human mammal, the germ cells and somatic cells of which contain an inactivated HMGI gene sequence introduced into the mammal, or an ancestor of the mammal, at an embryonic stage. The present invention also pertains to a method for treating obesity in a mammal which comprises reducing the biological activity of HMGI genes in the mammal. The present invention further pertains to a method for regulating growth and development of adipose tissue in a mammal which comprises reducing the biological activity of HMGI genes in the mammal. The present invention also pertains to a method for screening candidate compounds capable of inhibiting HMGI biological activity. The present invention also pertains to a mammal whose genome does not encode for both the functionally active leptin gene and the functionally active HMGI genes.

Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . A transgenic non-human mammal, the germ cells and somatic cells of which contain an inactivated HMGI gene sequence introduced into the mammal, or an ancestor of the mammal, at an embryonic stage.  
     
     
         2 . The mammal according to  claim 1 , wherein the inactivated HMGI gene sequence is an inactivated HMGI-C gene sequence.  
     
     
         3 . The mammal according to  claim 2 , wherein the inactivated HMGI-C gene sequence is the sequence of the mutant HMGI-C gene set out in FIG. 10.  
     
     
         4 . The mammal according to  claim 1 , wherein the mammal is a rodent.  
     
     
         5 . The mammal according to  claim 4 , wherein the rodent is a mouse.  
     
     
         6 . A method for treating obesity in a mammal which comprises reducing the biological activity of HMGI genes in the mammal.  
     
     
         7 . The method according to  claim 6 , wherein at least 10% of the biological activity of HMGI genes is reduced.  
     
     
         8 . The method according to  claim 7 , wherein at least 25% of the biological activity of HMGI genes is reduced.  
     
     
         9 . The method according to  claim 8 , wherein at least 50% of the biological activity of HMGI genes is reduced.  
     
     
         10 . The method according to  claim 6 , wherein the biological activity of HMGI-C genes is reduced.  
     
     
         11 . The method according to  claim 6 , wherein the mammal is leptin-deficient or leptin receptor-deficient.  
     
     
         12 . The method according to  claim 6 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the expression of HMGI genes.  
     
     
         13 . The method according to  claim 12 , wherein inhibition of the expression of HMGI genes is achieved by administering to the mammal a therapeutically effective amount of an oligonucleotide which has a nucleotide sequence complementary to at least a portion of the mRNA of the HMGI gene.  
     
     
         14 . The method according to  claim 6 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the DNA-binding activity of HMGI genes.  
     
     
         15 . The method according to  claim 14 , wherein the inhibition of the DNA-binding activity of HMGI genes is achieved by administering to the mammal a therapeutically effective amount of netropsin, distamycin A, or Hoechst 33258 (bisbenzimide).  
     
     
         16 . The method according to  claim 6 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the protein-protein interactions of HMGI proteins.  
     
     
         17 . The method according to  claim 6 , wherein the mammal is a human.  
     
     
         18 . The method according to  claim 6 , wherein the mammal is a rodent.  
     
     
         19 . The method according to  claim 18 , wherein the rodent is a mouse.  
     
     
         20 . The method according to  claim 18 , wherein the biological activity of HMGI is substantially reduced by breeding the mammal with an inactivated HMGI gene sequence introduced into the mammal, or an ancestor of the mammal, at an embryonic stage.  
     
     
         21 . The method according to  claim 20 , wherein the inactivated HMGI gene sequence is an inactivated HMGI-C gene sequence.  
     
     
         22 . The method according to  claim 21 , wherein the inactivated HMGI-C gene sequence is the sequence of the mutant HMGI-C gene set out in FIG. 10.  
     
     
         23 . A method for regulating growth and development of adipose tissue in a mammal which comprises reducing the biological activity of HMGI genes in the mammal.  
     
     
         24 . The method according to  claim 23 , wherein the mammal is leptin-deficient or leptin receptor-deficient.  
     
     
         25 . The method according to  claim 23 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the expression of HMGI genes.  
     
     
         26 . The method according to  claim 25 , wherein inhibition of the expression of HMGI genes is achieved by administering to the mammal a therapeutically effective amount of an oligonucleotide which has a nucleotide sequence complementary to at least a portion of the mRNA of the HMGI gene.  
     
     
         27 . The method according to  claim 23 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the DNA-binding activity of HMGI genes.  
     
     
         28 . The method according to  claim 27 , wherein the inhibition of the DNA-binding activity of HMGI genes is achieved by administering to the mammal a therapeutically effective amount of netropsin, distamycin A, or Hoechst 33258 (bisbenzimide).  
     
     
         29 . The method according to  claim 23 , wherein the reduction in biological activity of HMGI genes is achieved by inhibiting the protein-protein interactions of HMGI proteins.  
     
     
         30 . The method according to  claim 23 , wherein at least 10% of the biological activity of HMGI genes is reduced.  
     
     
         31 . The method according to  claim 30 , wherein at least 25% of the biological activity of HMGI genes is reduced.  
     
     
         32 . The method according to  claim 31 , wherein at least 50% of the biological activity of HMGI genes is reduced.  
     
     
         33 . A method for screening candidate compounds capable of inhibiting HMGI biological activity which comprises the steps of: 
 (a) immobilizing a HMGI protein or a fragment thereof on a solid surface;    (b) incubating the HMGI protein with a candidate compound under conditions which promote optimal interaction; and    (c) measuring the binding affinity of the candidate compound to the HMGI protein or a fragment whereof; and    (d) determining from the binding affinity which candidate compounds inhibit the HMGI biological activity.    
     
     
         34 . The method according to  claim 33 , wherein the candidate compound inhibits HMGI biological activity in an amount of at least 10%.  
     
     
         35 . The method according to  claim 34 , wherein the candidate compound inhibits HMGI biological activity in an amount of at least 25%.  
     
     
         36 . A method for screening candidate compounds capable of inhibiting HMGI biological activity which comprises the steps of: 
 (a) transfecting into a cell a DNA construct which contains a reporter gene under control of an HMGI protein-regulated promoter;    (b) administering to the cell a candidate compound;    (c) measuring the levels of reporter gene expression; and    (d) determining from the levels of reporter gene expression which candidate compounds inhibit the HMGI biological activity.    
     
     
         37 . The method according to  claim 36 , wherein the candidate compound inhibits HMGI biological activity in an amount of at least 10%.  
     
     
         38 . The method according to  claim 37 , wherein the candidate compound inhibits HMGI biological activity in an amount of at least 25%.  
     
     
         39 . A mammal whose genome does not encode for both the functionally active leptin gene and the functionally active HMGI genes.  
     
     
         40 . The mammal according to  claim 39 , wherein the HMGI gene is the HMGI-C gene.

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