Genes and proteins predictive and therapeutic for stroke, hypertension, diabetes and obesity

Abstract

Common human diseases like diabetes and hypertension have been demonstrated to possess an associated genetic component composed of numerous underlying genetic defects. Traditional positional cloning of genes which possess the mutations responsible for complex disease has been hindered by both the low statistical power each locus may afford, and by the technically-laborious nature of the positional cloning methodologies. Disclosed herein is a methodology for the rapid identification of the genes responsible for quantitative trait loci (QTL) comprised of comprehensive gene expression analysis in organs relevant to disease in combination with the positional mapping of known QTL, so as to quantitatively identify candidate genes. This aforementioned methodology was applied to a total of five tissues/organs derived from the spontaneously hypertensive rat (SHR), the stroke-prone variant of the SHR (SHR-SP) and control Wistar Kyoto rats (WKY). Collectively these animals vary genetically in their predisposition to stroke, insulin sensitivity, blood pressure and body weight. These traits segregate into more than a dozen identified. The present invention discloses the differential-expression of sixty genes by GeneCalling® within five different tissues/organs among these animals. Additionally, five of the sixty genes were demonstrated to be localized within chromosomal regions linked to these traits of interest and possess amino acid substitutions which may contribute to the phenotype.

What is claimed is:  
     
         1 . Isolated mutant proteins selected from a group consisting of: SGLT2, kynurenine aminotransferase, FAT/CD36, aldolase A, prepronatriodilatin, α-cardiac myosin and α-tubulin; wherein the amino acid sequences of said mutant proteins possess one or more amino acid substitutions in comparison to the amino acid sequence of the corresponding native protein.  
     
     
         2 . The isolated mutant proteins of  claim 1 , wherein said mutant proteins are human proteins possessing the amino acid sequences depicted in FIG. 4 consisting of: SGLT2 [SEQ ID NO:1]; kynurenine aminotransferase [SEQ ID NO:2]; FAT/CD36 [SEQ ID NOS:3 AND 4]; aldolase A [SEQ ID NO:5]; prepronatriodilatin [SEQ ID NO:6]; α-cardiac myosin [SEQ ID NO:7] and α-tubulin [SEQ ID NO:8].  
     
     
         3 . The isolated mutant proteins of  claim 1 , wherein said mutant proteins are substantially-purified proteins.  
     
     
         4 . Antibodies which are specific for, and possess the ability to bind to said mutant proteins of  claim 1 .  
     
     
         5 . Isolated nucleic acid sequences encoding said mutant proteins of  claim 1 .  
     
     
         6 . Antibodies which are specific for, and possess the ability to bind to said nucleic acid sequences of  claim 5 .  
     
     
         7 . Isolated anti-sense nucleic acid derivatives of the nucleic acid sequences encoding said mutant proteins of  claim 1 .  
     
     
         8 . Antibodies which are specific for, and possess the ability to bind to said anti-sense nucleic acid derivatives of  claim 7 .  
     
     
         9 . The mutant proteins of  claim 1 , wherein said mutant proteins possess a longer biological half life in vivo, relative to the corresponding, native human proteins.  
     
     
         10 . A method of treating or preventing hypertension comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said mutant proteins of  claim 1 , sufficient to treat or prevent hypertension.  
     
     
         11 . A method of treating or preventing hypertension comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more antibodies specific for, and possessing the ability to bind to one or more of said mutant proteins of  claim 1  sufficient to treat or prevent hypertension.  
     
     
         12 . A method of treating or preventing hypertension comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said nucleic acids of  claim 5 , sufficient to treat or prevent hypertension.  
     
     
         13 . A method of treating or preventing hypertension comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said anti-sense nucleic acid derivatives of  claim 7 , sufficient to treat or prevent hypertension.  
     
     
         14 . A method of treating or preventing diabetes and insulin resistivity comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said mutant proteins of  claim 1 , sufficient to treat or prevent diabetes and insulin resistivity.  
     
     
         15 . A method of treating or preventing diabetes and insulin resistivity comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more antibodies specific for, and possessing the ability to bind to one or more of said mutant proteins of  claim 1  sufficient to treat or prevent diabetes and insulin resistivity.  
     
     
         16 . A method of treating or preventing diabetes and insulin resistivity comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said nucleic acids of  claim 5 , sufficient to treat or prevent diabetes and insulin resistivity.  
     
     
         17 . A method of treating or preventing diabetes and insulin resistivity comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said anti-sense nucleic acid derivatives of  claim 7 , sufficient to treat or prevent diabetes and insulin resistivity.  
     
     
         18 . A method of treating or preventing obesity and dyslipidemia comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said mutant proteins of  claim 1 , sufficient to treat or prevent obesity and dyslipidemia.  
     
     
         19 . A method of treating or preventing obesity and dyslipidemia comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more antibodies specific for, and possessing the ability to bind to one or more of said mutant proteins of  claim 1  sufficient to treat or prevent obesity and dyslipidemia.  
     
     
         20 . A method of treating or preventing obesity and dyslipidemia comprising of administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said nucleic acids of  claim 5 , sufficient to treat or prevent obesity and dyslipidemia.  
     
     
         21 . A method of treating or preventing obesity and dyslipidemia comprising administering, to a subject in which such treatment or prevention is desired, an amount of one or more of said anti-sense nucleic acid derivatives of  claim 7 , sufficient to treat or prevent obesity and dyslipidemia.  
     
     
         22 . A method of treating or preventing or delaying stroke comprising of administering, to a subject in which such treatment or prevention or delay is desired, an amount of one or more of said mutant proteins of  claim 1 , sufficient to treat or prevent sufficient to treat or prevent or delay stroke.  
     
     
         23 . A method of treating or preventing or delaying stroke comprising of administering, to a subject in which such treatment or prevention or delay is desired, an amount of one or more antibodies specific for, and possessing the ability to bind to one or more of said mutant proteins of  claim 1  sufficient to treat or prevent or delay stroke.  
     
     
         24 . A method of treating or preventing or delaying stroke comprising of administering, to a subject in which such treatment or prevention or delay is desired, an amount of one or more of said nucleic acids of  claim 5 , sufficient to treat or prevent sufficient to treat or prevent or delay stroke.  
     
     
         25 . A method of treating or preventing or delaying stroke comprising of administering, to a subject in which such treatment or prevention or delay is desired, an amount of one or more of said anti-sense nucleic acid derivatives of  claim 7 , sufficient to treat or prevent sufficient to treat or prevent or delay stroke.  
     
     
         26 . The method of  claim 22 , wherein said mutant prepronatriodilatin protein [SEQ ID NO:6] is administered to prevent stroke in a subject possessing one or more risk factors for stroke.  
     
     
         27 . The method of  claim 22 , wherein said stroke is ischemic stroke.  
     
     
         28 . The method of  claim 22 , wherein said mutant human prepronatriodilatin [SEQ ID NO:6] increases latency to stroke in stroke-prone rats fed a high salt diet.  
     
     
         29 . A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of one or more of said mutant proteins of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         30 . A kit, comprising in one or more containers, a therapeutically or prophylactically effective amount of the pharmaceutical composition of  claim 29 .  
     
     
         31 . A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of one or more of said nucleic acid of  claim 5 , and a pharmaceutically acceptable carrier.  
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein said nucleic acid is a nucleic acid vector.  
     
     
         33 . A kit, comprising in one or more containers, a therapeutically or prophylactically effective amount of the pharmaceutical composition of  claim 31 .  
     
     
         34 . A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of one or more antibodies which are specific for, and possess the ability to bind to, one or more of said mutant proteins of  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         35 . A kit, comprising in one or more containers, a therapeutically or prophylactically effective amount of the pharmaceutical composition of  claim 34 .  
     
     
         36 . A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of one or more of said anti-sense nucleic acid derivatives of  claim 7 , and a pharmaceutically acceptable carrier.  
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein said anti-sense nucleic acid derivative is a nucleic acid vector.  
     
     
         38 . A kit, comprising in one or more containers, a therapeutically or prophylactically effective amount of the pharmaceutical composition of  claim 36 .  
     
     
         39 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant SGLT2 allele, the presence of said mutant SGLT2 allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         40 . The method of  claim 39  in which said mutant SGLT2 allele encodes a mutant SGLT2 having an amino acid substitution corresponding to the amino acid sequence of human SGLT2 as depicted in FIG. 4 (SEQ ID NO:1).  
     
     
         41 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant kynurenine aminotransferase allele, the presence of said mutant kynurenine aminotransferase allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         42 . The method of  claim 41  in which said mutant kynurenine aminotransferase allele encodes a mutant kynurenine aminotransferase having an amino acid substitution corresponding to the amino acid sequence of human kynurenine aminotransferase as depicted in FIG. 4 (SEQ ID NO:2).  
     
     
         43 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant FAT/CD36 allele, the presence of said mutant FAT/CD36 allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         44 . The method of  claim 43  in which said mutant FAT/CD36 allele encodes a mutant FAT/CD36 having an amino acid substitution corresponding to the amino acid sequence of human FAT/CD36 as depicted in FIG. 4 (SEQ ID NO:3 and NO:4).  
     
     
         45 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant aldolase A allele, the presence of said mutant aldolase A allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         46 . The method of  claim 45  in which said mutant aldolase A allele encodes a mutant aldolase A having an amino acid substitution corresponding to the amino acid sequence of human aldolase A as depicted in FIG. 4 (SEQ ID NO:5).  
     
     
         47 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant prepronatriodilatin allele, the presence of said mutant prepronatriodilatin allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         48 . The method of  claim 47  in which said mutant prepronatriodilatin allele encodes a mutant prepronatriodilatin having an amino acid substitution corresponding to the amino acid sequence of human prepronatriodilatin as depicted in FIG. 4 (SEQ ID NO:6).  
     
     
         49 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant α-cardiac myosin allele, the presence of said mutant α-cardiac myosin allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         50 . The method of  claim 49  in which said mutant α-cardiac myosin allele encodes a mutant α-cardiac myosin having an amino acid substitution corresponding to the amino acid sequence of human α-cardiac myosin as depicted in FIG. 4 (SEQ ID NO:7).  
     
     
         51 . A method for screening for an allele protective against hypertension, diabetes, obesity and/or stroke in a subject comprising detecting a mutant α-tubulin allele, the presence of said mutant α-tubulin allele being indicative of an allele protective for hypertension, diabetes, obesity and/or stroke.  
     
     
         52 . The method of  claim 51  in which said mutant α-tubulin allele encodes a mutant α-tubulin having an amino acid substitution corresponding to the amino acid sequence of human α-tubulin as depicted in FIG. 4 (SEQ ID NO:8).  
     
     
         53 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant SGLT2 protein of  claim 1  comprising: 
 (a) administering a putative modulator of SGLT2 activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with SGLT2 activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates SGLT2 activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         54 . The method of  claim 53 , wherein said test animal is a recombinant test animal which expresses an SGLT2 transgene or expresses SGLT2 under the control of a promoter which is not the native SGLT2 gene promoter at an increased level relative to a wild-type test animal.  
     
     
         55 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant kynurenine aminotransferase protein of  claim 1  comprising: 
 (a) administering a putative modulator of kynurenine aminotransferase activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with kynurenine aminotransferase activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates kynurenine aminotransferase activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         56 . The method of  claim 55 , wherein said test animal is a recombinant test animal which expresses a kynurenine aminotransferase transgene or expresses kynurenine aminotransferase under the control of a promoter which is not the native kynurenine aminotransferase gene promoter at an increased level relative to a wild-type test animal.  
     
     
         57 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant FAT/CD36 protein of  claim 1  comprising: 
 (a) administering a putative modulator of FAT/CD36 activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with FAT/CD36 activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates FAT/CD36 activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         58 . The method of  claim 57 , wherein said test animal is a recombinant test animal which expresses a FAT/CD36 transgene or expresses FAT/CD36 under the control of a promoter which is not the native FAT/CD36 gene promoter at an increased level relative to a wild-type test animal.  
     
     
         59 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant aldolase A protein of  claim 1  comprising: 
 (a) administering a putative modulator of aldolase A activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with aldolase A activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates aldolase A activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         60 . The method of  claim 59 , wherein said test animal is a recombinant test animal which expresses an aldolase A transgene or expresses aldolase A under the control of a promoter which is not the native aldolase A gene promoter at an increased level relative to a wild-type test animal.  
     
     
         61 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant prepronatriodilatin protein of  claim 1  comprising: 
 (a) administering a putative modulator of prepronatriodilatin activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with prepronatriodilatin activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates prepronatriodilatin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         62 . The method of  claim 61 , wherein said test animal is a recombinant test animal which expresses a prepronatriodilatin transgene or expresses prepronatriodilatin under the control of a promoter which is not the native prepronatriodilatin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         63 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant α-cardiac myosin protein of  claim 1  comprising: 
 (a) administering a putative modulator of α-cardiac myosin activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with α-cardiac myosin activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates α-cardiac myosin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         64 . The method of  claim 63 , wherein said test animal is a recombinant test animal which expresses an α-cardiac myosin transgene or expresses α-cardiac myosin under the control of a promoter which is not the native α-cardiac myosin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         65 . A method for screening for a modulator of the activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke of said mutant α-tubulin protein of  claim 1  comprising: 
 (a) administering a putative modulator of α-tubulin activity to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring one or more physiological parameters associated with α-tubulin activity, in which a change in said one or more parameters relative to an animal not administered the putative modulator indicates that the putative modulator modulates α-tubulin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
 
     
     
         66 . The method of  claim 65 , wherein said test animal is a recombinant test animal which expresses an α-tubulin transgene or expresses α-tubulin under the control of a promoter which is not the native α-tubulin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         67 . A method for screening a SGLT2 mutant for its SGLT2 activity comprising: 
 (a) administering the SGLT2 mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring stroke latency in the test animal, in which stroke latency is indicative of SGLT2 activity.    
     
     
         68 . The method of  claim 67  in which the test animal is a recombinant test animal which expresses an SGLT2 transgene or expresses SGLT2 under the control of a promoter which is not the native SGLT2 gene promoter at an increased level relative to a wild-type test animal.  
     
     
         69 . A method for screening a kynurenine aminotransferase mutant for its kynurenine aminotransferase activity comprising: 
 (a) administering the kynurenine aminotransferase mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of kynurenine aminotransferase activity.    
     
     
         70 . The method of  claim 69  in which the test animal is a recombinant test animal which expresses a kynurenine aminotransferase transgene or expresses kynurenine aminotransferase under the control of a promoter which is not the native kynurenine aminotransferase gene promoter at an increased level relative to a wild-type test animal.  
     
     
         71 . A method for screening a kynurenine aminotransferase mutant for its kynurenine aminotransferase activity comprising: 
 (a) administering the kynurenine aminotransferase mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of kynurenine aminotransferase activity.    
     
     
         72 . The method of  claim 71  in which the test animal is a recombinant test animal which expresses an kynurenine aminotransferase transgene or expresses kynurenine aminotransferase under the control of a promoter which is not the native kynurenine aminotransferase gene promoter at an increased level relative to a wild-type test animal.  
     
     
         73 . A method for screening a FAT/CD36 mutant for its kynurenine aminotransferase activity comprising: 
 (a) administering the FAT/CD36 mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of FAT/CD36 activity.    
     
     
         74 . The method of  claim 73  in which the test animal is a recombinant test animal which expresses a FAT/CD36 transgene or expresses FAT/CD36 under the control of a promoter which is not the native FAT/CD36 gene promoter at an increased level relative to a wild-type test animal.  
     
     
         75 . A method for screening a aldolase A mutant for its aldolase A activity comprising: 
 (a) administering the aldolase A mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of aldolase A activity.    
     
     
         76 . The method of  claim 75  in which the test animal is a recombinant test animal which expresses an aldolase A transgene or expresses aldolase A under the control of a promoter which is not the native aldolase A gene promoter at an increased level relative to a wild-type test animal.  
     
     
         77 . A method for screening a prepronatriodilatin mutant for its prepronatriodilatin activity comprising: 
 (a) administering the prepronatriodilatin mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and    (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of prepronatriodilatin activity.    
     
     
         78 . The method of  claim 77  in which the test animal is a recombinant test animal which expresses a prepronatriodilatin transgene or expresses prepronatriodilatin under the control of a promoter which is not the native prepronatriodilatin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         79 . A method for screening an α-cardiac myosin mutant for its prepronatriodilatin activity comprising: 
 (a) administering the α-cardiac myosin mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of α-cardiac myosin activity.  
 
     
     
         80 . The method of  claim 79  in which the test animal is a recombinant test animal which expresses an α-cardiac myosin transgene or expresses α-cardiac myosin under the control of a promoter which is not the native α-cardiac myosin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         81 . A method for screening an α-tubulin mutant for its prepronatriodilatin activity comprising: 
 (a) administering the α-tubulin mutant to a test animal prone to hypertension, diabetes, obesity and/or stroke; and  
 (b) measuring the latency of hypertension, diabetes, obesity and/or stroke in the test animal, wherein such latency is indicative of α-tubulin activity.  
 
     
     
         82 . The method of  claim 81  in which the test animal is a recombinant test animal which expresses an α-tubulin transgene or expresses α-tubulin under the control of a promoter which is not the native α-tubulin gene promoter at an increased level relative to a wild-type test animal.  
     
     
         83 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal, which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of SGLT2 activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate SGLT2 activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         84 . The method of  claim 83  in which said SGLT2 mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         85 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal, which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of kynurenine aminotransferase activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate kynurenine aminotransferase activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         86 . The method of  claim 85  in which said kynurenine aminotransferase mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         87 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal. which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of FAT/CD36 activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate FAT/CD36 activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         88 . The method of  claim 87  in which said FAT/CD36 mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         89 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal. which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of aldolase A activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate aldolase A activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         90 . The method of  claim 89  in which said aldolase A mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         91 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal, which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of prepronatriodilatin activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate prepronatriodilatin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         92 . The method of  claim 91  in which said prepronatriodilatin mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         93 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal, which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of α-cardiac myosin activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate α-cardiac myosin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         94 . The method of  claim 93  in which said α-cardiac myosin mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         95 . A method for screening for a modulator of activity or of latency or predisposition to hypertension, diabetes, obesity and/or stroke comprising measuring such latency in a test animal, which is prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke, and which recombinantly-expresses a putative modulator of α-tubulin activity, wherein a change in the latency of hypertension, diabetes, obesity and/or stroke within said test animal relative to an analogous animal which is also prone or predisposed to the development of hypertension, diabetes, obesity and/or stroke but does not recombinantly-express the putative modulator, is indicative of the putative modulator possessing the ability to modulate α-tubulin activity or latency or predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         96 . The method of  claim 95  in which said α-tubulin mutant is screened for an increase in the latency or a decrease in predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         97 . A recombinant, non-human animal possessing a mutant SGLT2 gene which is under the control of a promoter which is not the native SGLT2 gene promoter, wherein said mutant SGLT2 gene encodes a mutant SGLT2 which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         98 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant SGLT2 gene sequence.  
     
     
         99 . A recombinant, non-human animal possessing a mutant kynurenine aminotransferase gene which is under the control of a promoter which is not the native kynurenine aminotransferase gene promoter, wherein said mutant kynurenine aminotransferase gene encodes a mutant kynurenine aminotransferase which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         100 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant kynurenine aminotransferase gene sequence.  
     
     
         101 . A recombinant, non-human animal possessing a mutant FAT/CD36 gene which is under the control of a promoter which is not the native FAT/CD36 gene promoter, wherein said mutant FAT/CD36 gene encodes a mutant FAT/CD36 which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         102 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant FAT/CD36 gene sequence.  
     
     
         103 . A recombinant, non-human animal possessing a mutant aldolase A gene which is under the control of a promoter which is not the native aldolase A gene promoter, wherein said mutant aldolase A gene encodes a mutant aldolase A which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         104 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant aldolase A gene sequence.  
     
     
         105 . A recombinant, non-human animal possessing a mutant prepronatriodilatin gene which is under the control of a promoter which is not the native prepronatriodilatin A gene promoter, wherein said mutant prepronatriodilatin A gene encodes a mutant prepronatriodilatin which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         106 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant prepronatriodilatin gene sequence.  
     
     
         107 . A recombinant, non-human animal possessing a mutant α-cardiac myosin gene which is under the control of a promoter which is not the native α-cardiac myosin gene promoter, wherein said mutant α-cardiac myosin gene encodes a mutant α-cardiac myosin which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         108 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant α-cardiac myosin gene sequence.  
     
     
         109 . A recombinant, non-human animal possessing a mutant α-tubulin gene which is under the control of a promoter which is not the native α-tubulin gene promoter, wherein said mutant α-tubulin gene encodes a mutant α-tubulin which either increases the latency or decreases the predisposition to hypertension, diabetes, obesity and/or stroke.  
     
     
         110 . A recombinant, non-human animal which is the product of a process comprising introducing a nucleic acid into said non-human animal, or an ancestor thereof, wherein said nucleic acid comprises a mutant α-tubulin gene sequence.