Transgenic animal model of mood disorders

Abstract

A non-human transgenic animal having a polynucleotide encoding a PTN polypeptide, which polynucleotide is operably linked to a promoter, wherein said transgenic animal has greater than wild-type expression of the PTN polypeptide in at least one brain region, as well as related vectors, methods of producing transgenic animals, in vitro and in vivo screening methods for potential therapeutic agents, and methods for treating and diagnosing neuropsychiatric illnesses, particularly anxiety and depression, are disclosed.

1 . A method of assessing the presence of or susceptibility to anxiety and/or depression, in a human test subject, comprising:
 detecting and/or determining the amount of a Pleiotrophin (PTN) polypeptide in a sample which has been obtained from said test subject; and   comparing said amount of the PTN polypeptide with one or more reference values corresponding to the amount of the PTN polypeptide in a control sample obtained from a control subject not having a neuropsychiatric illness, wherein an increase of at least 10% in said amount of the PTN polypeptide in the sample which has been obtained from said test subject compared to said reference value indicates the presence of or susceptibility to anxiety and/or depression in the subject, and wherein said sample is selected from the group consisting of: blood, plasma, serum, cerebrospinal fluid (CSF) and central nervous system tissue.   
     
     
         2 . The method of  claim 1 , wherein the test subject has not previously been diagnosed as having a neuropsychiatric illness. 
     
     
         3 . The method of  claim 1 , wherein the test subject has previously been diagnosed as having a neuropsychiatric illness, and wherein said method is a method of assessing the stage and/or severity of the illness, to select the patients that will benefit from treatment or to monitor the effect of a treatment administered to the test subject. 
     
     
         4 . The method of  claim 1 , wherein said depression is major depression. 
     
     
         5 . The method of  claim 1 , wherein the amount of PTN polypeptide in the sample which has been obtained from said test subject is determined to be at least 20% higher than said reference value. 
     
     
         6 . The method of  claim 1 , wherein the method comprises contacting the sample with one or more antibodies specific for PTN polypeptide, allowing said one or more antibodies to form a complex with the PTN polypeptide, and quantifying the antibody-PIN protein complex, thereby determining the amount of PTN polypeptide in the sample. 
     
     
         7 . The method of  claim 6 , wherein the method employs a technique selected from the group consisting of: Western blot, Western transfer, Enzyme-Linked Immunosorbent Assay (ELISA), Radioimmunoassay (RIA), competitive enzyme immunoassay (EIA) and double antibody sandwich-ELISA (DAS-ELISA). 
     
     
         8 . The method of  claim 1 , wherein the method comprises extracting protein from the sample and mixing the protein extract with one or more antibodies specific for PTN polypeptide, allowing said one or more antibodies to form a complex with the PTN polypeptide and quantifying the antibody-PTN protein complex, thereby determining the amount of PTN polypeptide in the sample. 
     
     
         9 . The method of  claim 6 , wherein at least one of said one or more antibodies specific for PTN polypeptide is a goat polyclonal antibody available as product AF-252-PB from R&D Systems. 
     
     
         10 . The method of  claim 1 , wherein determining the amount of PTN polypeptide in the sample comprises subjecting the sample, or a protein extract obtained from the sample, to mass spectrometry analysis and quantifying the amount of PTN polypeptide detected. 
     
     
         11 . A method of assessing the presence of or susceptibility to anxiety and/or depression, in a human test subject, comprising:
 detecting and/or determining the amount of an mRNA or cDNA encoding a Pleiotrophin (PTN) polypeptide in a sample which has been obtained from said test subject; and   comparing said amount of the mRNA or cDNA encoding the PTN polypeptide with one or more reference values corresponding to the amount of the mRNA or cDNA encoding the PTN polypeptide in a control sample obtained from a control subject not having a neuropsychiatric illness, wherein an increase of at least 10% in said amount of the mRNA or cDNA encoding the PTN polypeptide in the sample which has been obtained from said test subject compared to said reference value indicates the presence of or susceptibility to anxiety and/or depression in the subject, and wherein said sample is selected from the group consisting of: blood, plasma, serum, cerebrospinal fluid (CSF) and central nervous system tissue.   
     
     
         12 . The method of  claim 11 , wherein the test subject has not previously been diagnosed as having a neuropsychiatric illness. 
     
     
         13 . The method of  claim 11 , wherein the test subject has previously been diagnosed as having a neuropsychiatric illness, and wherein said method is a method of assessing the stage and/or severity of the illness, to select the patients that will benefit from treatment or to monitor the effect of a treatment administered to the test subject. 
     
     
         14 . The method of  claim 11 , wherein said depression is major depression. 
     
     
         15 . The method of  claim 11 , wherein the amount of the mRNA or cDNA encoding the PTN polypeptide in the sample which has been obtained from said test subject is determined to be at least 20% higher than said reference value. 
     
     
         16 . The method of  claim 11 , wherein the method comprises extracting RNA from the sample, reverse transcribing the RNA to form cDNA, and amplifying the PTN polypeptide-encoding cDNA by polymerase chain reaction (PCR) using oligonucleotide primers, thereby determining the amount of the mRNA or cDNA encoding the PTN polypeptide in the sample. 
     
     
         17 . The method of  claim 16 , wherein said PCR is real-time quantitative PCR.