CN1739805A - Composition and method of diagnosing and treating type-II diabetes and sugar tolerance abnormality - Google Patents
Composition and method of diagnosing and treating type-II diabetes and sugar tolerance abnormality Download PDFInfo
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- CN1739805A CN1739805A CN 200410064186 CN200410064186A CN1739805A CN 1739805 A CN1739805 A CN 1739805A CN 200410064186 CN200410064186 CN 200410064186 CN 200410064186 A CN200410064186 A CN 200410064186A CN 1739805 A CN1739805 A CN 1739805A
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Abstract
The present invention relates to composition and method of diagnosing and treating type-II diabetes and sugar tolerance abnormality, and discloses the application of PAX6 gene or PAX6 activity and/or expression reinforcer in preparing medicine for treating type-II diabetes and sugar tolerance abnormality, the medicine prepared therewith and the treatment method, the method of diagnosing and treating type-II diabetes and sugar tolerance abnormality via detecting the degradation of PAX6 activity and/or expression in the sample, and the diagnosing composition and method generated therewith.
Description
Invention field
The present invention relates to be used to diagnose and treat the compositions and the method for type 2 diabetes mellitus and impaired glucose tolerance, particularly, relate to purposes and the consequent method and composition of PAX6 gene in type 2 diabetes mellitus or impaired glucose tolerance diagnosis and treatment.
Background technology
The PAX6 gene, clone's in 1991 a gene that plays an important role in eyes and neurodevelopment process is a kind of transcription factor, is made up of in conjunction with territory and transcription activating domain DNA to the C-end from the N-end.DNA can combine PAX6 with target gene DNA in conjunction with the territory, and transcription activating domain can make PAX6 activate the expression of downstream gene.PAX6 gene knockout animal can not grow eyes and brain, just can not survive in the birth back.
Nearest some studies show that the PAX6 gene also plays an important role in the pancreas growth course and on the function.The deratization of PAX6 clpp gene can not form α cell and islets of langerhans paramophia.In conjunction with the territory the synthetic premature termination of albumen that nonsense mutation is PAX6 taking place at the PAX6 gene DNA, makes it have only the DNA combined function and lose transcriptional activation function, the Sey of homozygous mutation
NeuThe quantity that Mus then can cause expressing the β cell of the α cell of glucagon and expression of insulin all has tangible reduction, and the expression of insulin is less than normal 10%, the Sey of heterozygous mutant
NeuThe expression of Mus insulin also has reduction.In vitro study shows that also the expression of PAX6 gene pairs glucagon and insulin gene has regulating and controlling effect.The growth that all these data show PAX6 gene pairs pancreas especially the α cell be formed with important function; The performance of the normal function of the pancreas especially function of β cell there is regulating and controlling effect.All these data show that the PAX6 gene mutation may cause the generation of diabetes.
Summary of the invention
It is the diagnostic method and the relative treatment measure of the type 2 diabetes mellitus or the impaired glucose tolerance of foundation with the PAX6 gene that main purpose of the present invention provides one.
The inventor finds that after deliberation PAX6 gene mutation meeting causes the generation of type 2 diabetes mellitus.Experiment shows patient's glucose in the body, and glucagon and insulin level and normal control more all have unusually.Experiment in vitro prompting PAX6 gene has lost the normal regulation effect to glucagon and insulin gene after DNA is in conjunction with the territory sudden change.
A first aspect of the present invention relates to the method for the treatment of type 2 diabetes mellitus or impaired glucose tolerance, and being included in to increase the active and/or expression of PAX6 in patient's body of treatment.Increasing PAX6 activity and/or expression can realize in the following way: for example, use PAX6 gene (comprising the normal or active PAX6 gene that improves) or contain this expression carrier to described patient, as recombinant viral vector (as adenovirus vector, retroviral vector or adeno-associated virus vector); Perhaps, use PAX6 activity and/or expression facilitator for described patient.
Term used herein " treatment " comprises the existing disease of prophylactic morbidity and treatment (as alleviate, alleviation etc.).The patient comprises any animal, preferred mammal, more preferably people.
If be fit to, " increasing the PAX6 activity " has identical implication with " increasing PAX6 expresses ", thereby is meant that increasing PAX6 gene expression increases the proteinic amount of PAX6, and/or increases the PAX6 activity of proteins.The method that increases PAX6 gene expression is well known in the art, for example can be by the copy number of normal in the employing DNA recombinant technique increase cell or the active PAX6 gene that improves, by utilizing modes such as strong promoter or enhancer to increase PAX6 gene transcription level, improve the stability of mRNA, increase translation skill or the translation post-treatment level of mRNA, perhaps increase methods such as proteinic stability of PAX6 or half-life, perhaps any combination of these methods increases PAX6 gene expression.
Increase the PAX6 activity of proteins and comprise any method that realizes that the PAX6 protein active increases in purpose cell or the tissue, this can the known method of employing itself realize.For example, improve the activity that this protein activation target gene is transcribed by transforming DNA in conjunction with territory or transcription activating domain.Perhaps, increase its activity by reinforcing agent or the stabilizing agent that gives the PAX6 protein active.
In a preferred embodiment, treat type 2 diabetes mellitus or impaired glucose tolerance by giving the normal or active PAX6 gene that improves.This can realize by the gene therapy method of routine.For example, can make up and contain this expression carrier, for example recombinant viral vector comes administration by the method that is suitable for this carrier and target cell then.
If suitably, the PAX6 active reinforcing agent has identical implication with the PAX6 expression facilitator, being meant to increase any material that PAX6 is active and/or increase PAX6 expresses.Example comprises that PAX6 mRNA stabilizing agent, protein active strengthen or stabilizing agent.
" the normal or active PAX6 gene that improves " is meant to have the active or more highly active PAX6 gene that has substantially the same level with normal PAX6 gene.The activity of PAX6 gene is meant that coding has the proteinic ability of bioactive PAX6.Normal or the active PAX6 gene that improves is maybe can obtaining of knowing of those skilled in the art, for example can make up the essentially identical gene that bioactive PAX6 is proteinic, have the different IPs nucleotide sequence that has of encoding, also can make up coding and having the proteinic gene of more highly active PAX6.The PAX6 gene comprises the DNA of its genomic DNA, cDNA, RNA such as mRNA, DNA analog, synthetic or the chemical compound of RNA or analog D NA or RNA etc.
In a preferred embodiment, described type 2 diabetes mellitus or impaired glucose tolerance are type 2 diabetes mellitus or the impaired glucose tolerance that PAX6 is active and/or the expression reduction causes.PAX6 is active and/or express to reduce and comprise that PAX6 gene expression reduces or completely lose and/or expressed protein is active reduces or completely lose.Protein active reduction or the example that completely loses are, the protein of PAX6 gene code sudden change, described sudden change comprises insertion, disappearance and/or replaces, nonsense mutation for example, for example at the nonsense mutation of DNA in conjunction with territory or transcription activating domain, cause protein to have the effect of the transcriptional activation of reduction, perhaps completely lose this effect.For example, PAX6 gene cDNA 1080 nucleotide C sport T, make that the arginic codon mutation of coding is a termination codon.
The present invention relates to PAX6 gene or PAX6 activity and/or expression facilitator on the other hand and is used for the treatment of purposes in the medicine of type 2 diabetes mellitus or impaired glucose tolerance in preparation.The preferably normal or active PAX6 gene that improves of PAX6 gene.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
The present invention relates to the medicine for the treatment of type 2 diabetes mellitus or impaired glucose tolerance on the other hand, and it contains normal or active PAX6 gene that improves and/or PAX6 activity and/or expression facilitator as active component.Randomly, can contain other excipient, diluent or carrier.Described medicine can adopt the conventional method preparation and use.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
The present invention relates to the method for the medicine of screening treatment type 2 diabetes mellitus or impaired glucose tolerance on the other hand, comprise that (1) is allowing to increase under the condition of PAX6 protein active or expression, cell or the tissue of test substance with PAX6 protein or its active part or expression PAX6 protein or its active part contacted, (2) measure PAX6 activity of proteins or expression, activity or expression increase show that this test substance has the potentiality of treatment type 2 diabetes mellitus or impaired glucose tolerance.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
The present invention relates to above-mentioned screening on the other hand and treats the medicine that the method for the medicine of type 2 diabetes mellitus or impaired glucose tolerance obtains.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
The present invention relates to medicine that the method for the medicine of above-mentioned screening treatment type 2 diabetes mellitus or impaired glucose tolerance obtains on the other hand and is used for the treatment of purposes in the medicine of type 2 diabetes mellitus or impaired glucose tolerance in preparation.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
Another aspect of the present invention relates to the method that diagnosis type 2 diabetes mellitus or impaired glucose tolerance or detection suffer from the danger of type 2 diabetes mellitus or impaired glucose tolerance, comprises the reduction that detection is active from PAX6 in patient's the sample and/or express." the active and/or expression reduction of PAX6 " is in above explanation.In a preferred embodiment, described diagnostic method comprises: (1) will contact with the instrument that detects the PAX6 activity and/or express from patient's sample; (2) the active and/or expression of detection PAX6, PAX6 reduction active and/or that express is indicated and is had type 2 diabetes mellitus or impaired glucose tolerance or have the danger of suffering from type 2 diabetes mellitus or impaired glucose tolerance in the sample.If suitably, above-mentioned preferred feature also is suitable for this on the one hand.
" detecting the instrument that PAX6 is active and/or express " is to detect any instrument (comprise and detect the reagent that PAX6 is active and/or express) that PAX6 is active and/or express, include but not limited to: the polyacrylamide gel that is used to detect the PCR primer and the hybridization probe of gene mutation and is used for detecting gene mutation by for example SSCP, be used to detect the PCR primer and the hybridization probe of mRNA amount, be used to detect the antibody or the antibody fragment of albumen quality, be used to detect gene or protein mutant (truncate, insert, disappearance, perhaps substitute) specific antibody or instrument, be used to detect the reagent of protein active, measure method of DNA or protein sequence or the like.
Another aspect of the present invention relates to the purposes of the diagnosis composition that detects the danger that PAX6 reagent active and/or that express is used in preparation diagnosing type 2 diabetes mellitus or impaired glucose tolerance or detection to suffer from type 2 diabetes mellitus or impaired glucose tolerance.If suitably, preferred feature mentioned above also is suitable for this on the one hand.
Another aspect of the present invention relates to and is used to diagnose type 2 diabetes mellitus or impaired glucose tolerance or detection to suffer from the diagnosis composition of the danger of type 2 diabetes mellitus or impaired glucose tolerance, and it comprises and detects the reagent that PAX6 is active and/or express.
The invention still further relates to the test kit that comprises above-mentioned diagnosis composition.
Description of drawings
Fig. 1: the big family family tree of diabetes.■ ● be expressed as diabetics,
Be the impaired glucose tolerance patient, zero expression normal person; 1, the position in the family of the individual place of 2......40 digitized representation family.
Fig. 2: the expression of sudden change PAX6 gene inhibition glucagon and insulin gene.The wild type PAX6 of vivoexpression and sudden change PAX6 see its expression regulation to the promoter of glucagon and insulin gene by measuring the Luciferase activity.Relative LuciferaseActivity: relative Luciferase activity.
The influence of A:PAX6 gene pairs glucagon gene expression.Wild type PAX6 makes glucagon expression of gene comparison reach 6.5 times according to raising, and sudden change PAX6 does not play any effect, shows that the gene that has suddenlyd change loses the normal regulation to the glucagon gene.Mock is a control plasmid among the figure; Wild-type PAX6 is a wild type PAX6 plasmid; MutatedPAX6 is sudden change PAX6 plasmid;-350GluLuc represents to have the promoter L uciferase expression plasmid of glucagon gene.
The influence that B:PAX6 gene pairs insulin gene is expressed.Wild type PAX6 and sudden change PAX6 and results of comparison do not have notable difference separately; Simultaneously PAX6 and NeuroD expression of gene plasmid are carried out transfection, wild type PAX6 makes 3.2 times of the up-regulateds of insulin gene as a result, and sudden change PAX6 does not play a significant role, and shows that the expression of PAX6 gene pairs insulin gene is influential equally.Mock is a control plasmid among the figure; Wild-type PAX6 is a wild type PAX6 plasmid; Mutated PAX6 is sudden change PAX6 plasmid; NeuroD is a NeuroD expression of gene plasmid;-410RIP1Luc represents to have the promoter L uciferase expression plasmid of insulin gene.
The specific embodiment
Embodiment 1:
The sudden change of PAX6 gene causes the generation of patient's impaired glucose tolerance and type 2 diabetes mellitus in a big family
(1) determining of PAX6 gene and mutational site thereof:
Extract the peripheral blood 2-5ml of family member, extract DNA; Genetic marker (STR labelling) with the PAX6 gene carries out linkage analysis to all members of family, judge that this family Disease-causing gene is the PAX6 gene, concrete operations: the primer of first Synthetic 2-3 a STR labelling carries out PCR (polymerase chain reaction), separate with degeneration PAGE (polyacrylamide) glue after the degeneration of PCR product, carry out linkage analysis with Linkage software according to the relation between banding pattern and family member; Determining of PAX6 mutational site, the primer of synthetic all exons of PAX6 gene carries out the PCR reaction, all PCR products carry out SSCP (single strand conformation polymorphism) and analyze, this family has only the 9th exon SSCP, and patient and normal control are variant as a result, determine that the position that sudden change takes place is the 9th exon, PCR product to the 9th exon checks order, and finding the mutational site is that PAX6 gene cDNA 1080 nucleotide C sport T, makes that the arginic codon mutation of coding is a termination codon.
(2) oral glucose tolerance experiment (OGTT):
After on an empty stomach more than 12 hours, venous blood samples 6ml extracts the venous blood 6ml of half an hour and 2 hours respectively behind oral glucose 75 grams, and separation of serum is measured glucose level to all blood samples, serves as according to judging ill situation with the clinical diagnosis standard.All members that the PAX6 gene mutation is arranged more than 30 years old all have in various degree impaired glucose tolerance even diabetes in this family (Fig. 1) as a result, and the patient below 30 years old is all normal at present, and all normal persons comprise 5 greater than 30 years old people then all normal (table 1).
(3) influence of the expression of Tu Bian PAX6 gene pairs glucagon and insulin gene:
Make up normal PAX6 and sudden change PAX6 expression of gene plasmid, in-vitro transfection advances 293 cells, sees its expression regulation to the promoter of glucagon and insulin gene by measuring the Luciferase activity.The normal PAX6 of result raises the glucagon expression of gene to reach 6.5 times, and sudden change PAX6 does not play any effect, shows that the gene that has suddenlyd change loses the normal regulation to the glucagon gene.For expression regulation to insulin gene, PAX6 is normal does not separately have notable difference with sudden change PAX6 and blank result, PAX6 might work in coordination with the expression that influences insulin with other transcription factor, therefore we carry out transfection with PAX6 and NeuroD expression of gene plasmid simultaneously, the normal PAX6 of result makes 3.2 times of the up-regulateds of insulin gene, and sudden change PAX6 does not play a significant role, and shows the expression influential equally (Fig. 2) of PAX6 gene pairs insulin gene.
Table 1. oral glucose tolerance experiment (OGTT) experimental result
M: man; F: woman; D: diabetes; IGT: sugar does not tolerate; NGT: normal sugar tolerance;
M: mutant gene; N: normal gene
| The member position | Age | Sex | BMI (kgm -2) | Glucose (mmol L -1) | Diagnostic result | Genotype | ||
| 0’ | 30’ | 120’ | ||||||
| 8 9 15 16 20 21 22 17 24 19 31 37 38 34 26 27 28 29 30 32 36 33 35 | 69 67 43 42 40 38 35 33 32 30 19 16 14 11 41 38 34 33 30 15 14 13 7 | M M F M M M F M F F M F M M M M M M M F M M M | 17.58 20.22 20.86 21.15 20.42 20.99 20.43 20.96 22.93 20.83 20.33 19.41 16.19 15.28 19.93 21.19 22.30 20.43 22.83 17.31 16.54 15.42 15.06 | 7.58 6.68 5.79 4.35 6.80 5.62 5.42 5.24 5.25 4.74 4.40 5.14 4.58 4.72 3.30 3.58 3.89 4.12 4.38 4.15 4.71 5.24 4.81 | 9.32 6.05 5.45 5.52 6.56 5.16 12.03 10.01 6.00 6.74 7.70 6.61 6.53 9.47 8.67 8.00 7.71 7.34 7.76 6.67 7.09 6.85 6.84 | 8.62 11.31 9.03 8.57 8.64 8.19 16.65 7.86 8.28 10.03 5.73 6.21 7.07 5.66 6.03 6.09 6.47 4.00 4.63 5.48 6.23 5.08 6.18 | D D IGT IGT IGT IGT D IGT IGT IGT NGT NGT NGT NGT NGT NGT NGT NGT NGT NGT NGT NGT NGT | m/N m/N m/N m/N m/N m/N m/N m/N m/N m/N m/N m/N m/N m/N N/N N/N N/N N/N N/N N/N N/N N/N N/N |
Claims (10)
1.PAX6 gene or PAX6 activity and/or expression facilitator are used for the treatment of purposes in the medicine of type 2 diabetes mellitus or impaired glucose tolerance in preparation.
2. treat the medicine of type 2 diabetes mellitus or impaired glucose tolerance, it contains normal or active PAX6 gene that improves and/or PAX6 activity and/or expression facilitator as active component, randomly, can contain other excipient, diluent or carrier.
3. the method for the medicine of type 2 diabetes mellitus or impaired glucose tolerance is treated in screening, comprise that (1) is allowing to increase under the condition of PAX6 protein active or expression, cell or the tissue of test substance with PAX6 protein or its active part or expression PAX6 protein or its active part contacted, (2) measure PAX6 activity of proteins or expression, activity or expression increase show that this test substance has the potentiality of treatment type 2 diabetes mellitus or impaired glucose tolerance.
4. screen the medicine that obtains according to claim 3 method.
5. the medicine of claim 4 is used for the treatment of purposes in the medicine of type 2 diabetes mellitus or impaired glucose tolerance in preparation.
6. diagnosis type 2 diabetes mellitus or impaired glucose tolerance or detection suffer from the method for the danger of type 2 diabetes mellitus or impaired glucose tolerance, comprise the reduction that detection is active from PAX6 in patient's the sample and/or express; Preferably, described diagnostic method comprises: (1) will contact with the instrument that detects the PAX6 activity and/or express from patient's sample; (2) the active and/or expression of detection PAX6, PAX6 reduction active and/or that express is indicated and is had type 2 diabetes mellitus or impaired glucose tolerance or have the danger of suffering from type 2 diabetes mellitus or impaired glucose tolerance in the sample; The example that wherein said expression reduces comprises the nonsense mutation of gene, for example at the nonsense mutation of DNA in conjunction with territory or transcription activating domain, cause protein to have the effect of the transcriptional activation of reduction, perhaps completely lose this effect, for example, PAX6 gene cDNA 1080 nucleotide C sport T, make that the arginic codon mutation of coding is a termination codon.
7. detect the purposes of the diagnosis composition of the danger that PAX6 reagent active and/or that express is used in preparation diagnosing type 2 diabetes mellitus or impaired glucose tolerance or detection to suffer from type 2 diabetes mellitus or impaired glucose tolerance.
8. be used to diagnose type 2 diabetes mellitus or impaired glucose tolerance or detection to suffer from the diagnosis composition of the danger of type 2 diabetes mellitus or impaired glucose tolerance, it comprises the reagent that detects the PAX6 activity and/or express.
9. the test kit that comprises the diagnosis composition of claim 8.
10. the invention of claim 1-9, wherein said type 2 diabetes mellitus or impaired glucose tolerance are type 2 diabetes mellitus or the impaired glucose tolerance that PAX6 is active and/or the expression reduction causes; The example that described expression reduces comprises the nonsense mutation of gene, for example at the nonsense mutation of DNA in conjunction with territory or transcription activating domain, cause protein to have the effect of the transcriptional activation of reduction, perhaps completely lose this effect, for example, PAX6 gene cDNA 1080 nucleotide C sport T, make that the arginic codon mutation of coding is a termination codon.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021155825A1 (en) * | 2020-02-08 | 2021-08-12 | 北京大学第三医院（北京大学第三临床医学院） | Use of pax6 gene or expression product thereof in preparation of drug for inhibiting fibrosis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021155825A1 (en) * | 2020-02-08 | 2021-08-12 | 北京大学第三医院（北京大学第三临床医学院） | Use of pax6 gene or expression product thereof in preparation of drug for inhibiting fibrosis |
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