Fgf2-related methods for diagnosing and treating depression

Abstract

The present application relates to the treatment and diagnosis of mood disorders, including bipolar disorder, major depression disorder and schizophrenia. The invention provides novel diagnostic markers and assays, as well as research tools for the development and discovery of agents and compounds which are useful for treating patients who suffer from mental illness.

1 . A method for facilitating the diagnosis of a mood disorder in a subject, comprising the steps of:
 (i) measuring the level of expression of a gene, wherein said gene is selected from the group consisting of the genes listed in  FIG. 5 ,  FIG. 6 ,  FIG. 7 ,  FIG. 8 ; Table Table 2B, Table 3, and Table 4;   (ii) determining whether said gene is dysregulated relative to a control, wherein dysregulation of said gene indicates an increased likelihood that said subject suffers from a mood disorder; and   (iii) recording or reporting any finding with respect to said increased likelihood.   
   
   
       2 . The method of  claim 1 , wherein said mood disorder is bipolar disorder, and said gene is selected from the group consisting of the genes listed in  FIG. 5 ,  FIG. 7 ,  FIG. 8 , Table 2B, and Table 4. 
   
   
       3 . The method of  claim 1 , wherein said mood disorder is major depression disorder and said gene is selected from the group consisting of the genes listed in  FIG. 6 ,  FIG. 8 , Table 1 and Table 3. 
   
   
       4 . The method of  claim 2  or  3 , wherein said gene dysregulation occurs in said subject's brain tissue. 
   
   
       5 . The method of  claim 4 , wherein said brain tissue is selected from the group consisting of the locus coeruleus, the dorsal raphe, the anterior cingulate cortex, the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. 
   
   
       6 . The method of  claim 2  or  3 , wherein said gene expression is assayed by detecting messenger RNA transcribed from said gene. 
   
   
       7 . The method of  claim 2  or  3 , wherein said gene expression is assayed by selectively detecting the protein product of said gene. 
   
   
       8 . The method of  claim 6 , wherein detecting messenger RNA transcribed from said gene comprises
 (i) contacting said mRNA with a reagent which selectively associates with said messenger RNA; and   (ii) detecting the level of said reagent which selectively associates with said mRNA.   
   
   
       9 . The method of  claim 1 , wherein the level of expression of said gene is higher than a level associated with humans without a mood disorder. 
   
   
       10 . The method of  claim 1 , wherein the level of expression of said gene is lower than a level associated with humans without a mood disorder. 
   
   
       11 . The method of  claim 1 , wherein the level of expression of said gene is detected using a microarray assay, and wherein said gene is one of at least two genes on the microarray. 
   
   
       12 . The method of  claim 1 , wherein said gene is selected from Table 1 and wherein said mood disorder is suicidal. 
   
   
       13 . The method of  claim 12 , wherein said subject was previously diagnosed with a mood disorder associated with an increased likelihood of suicidal activity. 
   
   
       14 . The method of  claim 12 , wherein said subject was previously diagnosed with a mood disorder selected from the group consisting of major depression, bipolar disorder, and schizophrenia. 
   
   
       15 . The method of  claim 12 , further comprising prescribing a treatment for said subject which reduces the likelihood of a suicide attempt by said subject. 
   
   
       16 . The method of  claim 1 , wherein said subject has symptoms of both bipolar disorder and major depressive disorder, and wherein said gene is differently expressed in bipolar subjects versus major depression disorder subjects, thereby facilitating a diagnosis of bipolar disorder or major depressive disorder in said subject. 
   
   
       17 . The method of  claim 1 , wherein said gene is dysregulated in substance-abusing MDD subjects versus MDD subjects who are not substance abusers, and wherein said gene is selected from the dysregulated genes listed in Table 1C, thereby facilitating a diagnosis of MDD versus MDD coupled with substance abuse. 
   
   
       18 . 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 corresponding to a dysregulated gene selected from the group of dysregulated genes listed in  FIG. 5 ,  FIG. 6 ,  FIG. 7 ,  FIG. 8 ; Table 2B, Table 3, and Table 4; and   (ii) determining the functional effect of the compound upon the polypeptide, thereby identifying a compound for treatment or prevention of a mood disorder.   
   
   
       19 . The method of  claim 18 , wherein the contacting step is performed in vitro. 
   
   
       20 . The method of  claim 18 , wherein the polypeptide is expressed in a cell and the cell is contacted with the compound. 
   
   
       21 . The method of  claim 18 , the mood disorder is selected from the group consisting of bipolar disorder, major depression disorder, suicidal, and substance abuse comorbidity. 
   
   
       22 . The method of  claim 18 , further comprising administering the compound to an animal and determining the effect on the animal. 
   
   
       23 . The method of  claim 22 , wherein the determining step comprises testing the animal's mental function. 
   
   
       24 . A method of treating a subject prone to suicide, the method comprising the step of administering to the subject a therapeutically effective amount of a polypeptide, the polypeptide encoded by a polynucleotide corresponding to a gene listed in Table 1 or Table 2. 
   
   
       25 . A method of treating symptoms of anxiety in a subject, comprising the step of administering a sufficient amount of FGF2 peptide to the subject after the subject has been diagnosed with anxiety or an illness associated with anxiety. 
   
   
       26 . The method of  claim 25 , wherein said subject is a human. 
   
   
       27 . The method of  claim 25 , wherein said sufficient amount is a dose administered at least twice weekly over a period at least one week in length. 
   
   
       28 . The method of  claim 25 , wherein said illness is Major Depression or Major Depressive Disorder. 
   
   
       29 . A method for identifying a human suffering from chronic stress comprising a) obtaining a nucleic acid sample from the subject; and b) determining the exon IIIb:IIIc splice variant ratio of the expressed gene selected from the group consisting of FGFR2 and FGFR3, wherein a ratio less than approximately 10 is associated with an increased likelihood that said human is suffering from chronic stress. 
   
   
       30 . The method of  claim 29 , wherein said gene is FGFR2. 
   
   
       31 . The method of  claim 29 , wherein said gene is FGFR3. 
   
   
       32 . The method of  claim 29 , wherein said method further comprises administering a pharmacological treatment in response to said identification. 
   
   
       33 . A method for identifying a compound which alters the exon IIIb:IIIc splice variant ratio of an expressed gene selected from the group consisting of FGFR2 and FGFR3 in a living animal, comprising
 a) identifying at least one animal suffering from chronic stress; b) measuring said splice variant ratio in said at least one animal; c) administering a test compound to said at least one animal; d) measuring said splice variant ratio a second time after said administration of said test compound; recording the identity of said test compound If said measurement shows that said splice variant ratio is increased.   
   
   
       34 . A method for treating a subject suffering from a glutamatergic imbalance comprising administering to the subject a sufficient amount of a compound which targets a molecule selected from the group consisting of: glial transporters, glutamine synthetase, AMPA, kainate, GRM1 and GRM7. 
   
   
       35 . A method for increasing neurite growth in a subject suffering from MDD, comprising administering to the subject a sufficient amount of a compound which targets FGFR3, TrkB receptor, or a growth hormone receptor, or which mimics the actions of FGF2. 
   
   
       36 . A method for detecting global glial alterations in a subject suffering from MDD, comprising the steps of determining the level of gene expression in the LC region of a subject, wherein said gene is a glial marker gene selected from the group of glial marker genes in Table 3. 
   
   
       37 . A method for distinguishing between BP and MDD in a human subject, comprising a) measuring the level of expression of at least one MDD- or BP-specific gene in DR tissue of said subject, wherein said MDD- or BP-specific gene is selected from the MDD- or BP-specific dysregulated genes listed in Table 4; b) and identifying an increased likelihood that said subject suffers from BP versus MDD, wherein downregulation of an MDD-specific gene in Table 4 correlates with an increased likelihood of MDD in said subject, and wherein downregulation of a BP-specific gene in Table 4 correlates with an increased likelihood of BP in said subject. 
   
   
       38 . A method for identifying a human subject with an increased risk of BP or MDD, comprising:
 (i) measuring the level of expression of a dysregulated gene selected from the genes listed in Table 3; and (ii) correlating said measurement with an increased risk of BP or MDD in said subject.   
   
   
       39 . The method of  claim 38 , further comprising recording or reporting said risk of developing BP or MDD. 
   
   
       40 . The method of  claim 38 , wherein said risk of developing bipolar disorder is reported to a physician or said human subject. 
   
   
       41 . A method for facilitating the diagnosis of major depression disorder in a subject, comprising the steps of:
 (i) measuring the ratio of expression of FGFR2 exon 5 to FGFR2 exon 11;   (ii) determining whether said ratio is lower than a control, wherein a lower ratio indicates an increased likelihood that said subject suffers from major depression disorder; and   (iii) recording or reporting any finding with respect to said increased likelihood.   
   
   
       42 . The method of  claim 41 , wherein said expression is in said subject's dorsolatereral prefrontal cortex. 
   
   
       43 . A method for facilitating the diagnosis of major depression disorder in a subject, comprising the steps of:
 (i) measuring the expression of FGFR2 exon 9;   (ii) determining whether said expression is lower than a control, wherein a lower level of expression indicates an increased likelihood that said subject suffers from major depression disorder; and   (iii) recording or reporting any finding with respect to said increased likelihood.   
   
   
       44 . The method of  claim 43 , wherein said expression is in said subject's dorsolatereral prefrontal cortex. 
   
   
       45 . A method for improving memory in a rodent, comprising
 administering FGF2 to said animal within 48 hours of birth of said animal.   
   
   
       46 . The method of  claim 45 , wherein said FGF2 is administered subcutaneously. 
   
   
       47 . The method of  claim 45 , wherein said FGF2 is administered at 20 ng/g body weight. 
   
   
       48 . A rodent which has been treated according to the methods of  claims 45 ,  46 , or  47 . 
   
   
       49 . The rodent of  claim 48 , wherein said rodent is an adult rodent, and wherein said rodent has improved memory relative to an untreated rodent; and wherein expression of NCAM in said rodent is decreased relative to an untreated rodent; and wherein expression of at least one gene selected from the group consisting of GAP-43, Rgs4, trkb, CCK, SST and Vgf is increased relative to an untreated rodent.