CN109234384A - HMGCL as diagnosis marker and therapy target Non-compaction type cardiomyopathy application - Google Patents
HMGCL as diagnosis marker and therapy target Non-compaction type cardiomyopathy application Download PDFInfo
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- CN109234384A CN109234384A CN201811327907.3A CN201811327907A CN109234384A CN 109234384 A CN109234384 A CN 109234384A CN 201811327907 A CN201811327907 A CN 201811327907A CN 109234384 A CN109234384 A CN 109234384A
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Abstract
Marker the invention discloses HMGCL as Non-compaction type diagnosis on primary cardiomyopathy and treatment.Present invention discover that HMGCL and the generation of Non-compaction type cardiomyopathy are closely related, therefore it has been put forward for the first time in the Related product for being applied to preparation diagnosis and treatment Non-compaction type cardiomyopathy using HMGCL as marker.This research provides new diagnosis index for the diagnosis of Non-compaction type cardiomyopathy, and provides new drug target to treat the drug development of Non-compaction type cardiomyopathy.
Description
Technical field
The present invention relates to the diagnosing and treating fields of cardiomyopathy, more particularly it relates to HMGCL gene expression and egg
Application of the white expression product as Non-compaction type diagnosis on primary cardiomyopathy marker and therapy target.
Background technique
Non-compaction type cardiomyopathy (left ventricular non-compaction cardiomyopathy,
It LVNC) is a kind of more rare cardiomyopathy, currently, checked since the clinical diagnosis of LVNC depends on ventricular morphology,
Lack diagnosis sign object, easily by mistaken diagnosis, and LVNC clinically there is no Specific Therapeutic methods.LVNC patients with clinical manifestations
In heterogeneity, some patientss can be asymptomatic throughout one's life, is only found in Cardiac ultrasound, and the another most of patients performance rhythm of the heart loses
Often, heart failure or even sudden cardiac death etc..
Although the mutation for having several genes is found in LVNC patient, so far, the molecular mechanism of LVNC is still not
It is clear.Therefore, relevant to LVNC morbidity candidate gene is found, it will help the molecule pathogenic mechanism for illustrating LVNC also will be
The diagnosing and treating of LVNC provides molecular marker.
Summary of the invention
The present invention relates to a kind of Non-compaction type cardiomyopathy (left ventricular non-compaction
Cardiomyopathy, LVNC) diagnosis marker and therapy target, the present invention pass through mass spectrometric data obtain HMGCL (3-
Hydroxy-3-methylglutaryl-CoA lyase) protein expression level in LVNC patient cardiac muscular tissue be substantially less than just
Normal cardiac muscular tissue, therefore HMGCL protein diversity expression property becomes and can be used to diagnose point whether subject suffers from LVNC
Sub- marker and the drug target for treating LVNC.
The present invention provides detection HMGCL protein expression product LVNC diagnosis in purposes.
The product can detect the protein expression variation of HMGCL in sample, the substance including that can combine HMGCL albumen；
Detection HMGCL protein expression product of the invention can be detected based on the method for antibody is used, including enzyme-linked
Immuno absorbence (enzyme-linked immuno sorbent assay, write a Chinese character in simplified form ELISA), elisa detection
(enzyme-linked immunospot assay, write a Chinese character in simplified form ELISPOT), radioimmunoassay (radioimmunoassay,
Write a Chinese character in simplified form RIA), immunohistochemical method (immuohistochemistry staining, write a Chinese character in simplified form IHC), immunoblotting
(western blot) can also carry out sxemiquantitative and quantitative analysis to albumen using protein chip and the method for mass spectral analysis.
The product that the present invention detects HMGCL albumen includes the antibody or antibody fragment for specifically binding HMGCL albumen, including
The corresponding nucleic of the amino acid sequence of encoding antibody or Encoding Antibody Fragment, the carrier comprising the nucleic acid and carry the carrier it is thin
Born of the same parents.
The antibody includes monoclonal antibody, polyclonal antibody, humanized antibody, double-chain antibody and single-chain antibody etc..It is anti-
Body segment refers to the antibody fragment with antigen active, including F (ab ')2, Fab ', Fab, single-chain antibody (single-chain
Antibody fragment/single-chain variable fragment, writes a Chinese character in simplified form scFv), disulfide bond stability antibody
(disulfide-stabilized Fv fragment, write a Chinese character in simplified form dsFv), Fv copolymer, the area dimerization V (double antibody) are contained
The antibody peptide fragment of antibody molecule complementarity determining region (complementarity-determining region, write a Chinese character in simplified form CDR).
Antibody can be obtained by the way that well known to a person skilled in the art methods.The method for preparing monoclonal antibody is such as
Under: using after antigen-immunized animal, from the immune animal adaptive immune cell of process and myeloma cell is merged to be hybridized
Oncocyte, then antibody is collected from Hybridoma Cell Culture object, the list for HMGCL albumen can be finally obtained by purification process
Clonal antibody.The preparation method of polyclonal antibody is as follows: antigen-immunized animal same as above is used, from process
Immune animal collects blood sample, separates serum, finally implements purifying to separated serum and obtains for HMGCL albumen
Polyclonal antibody.
The combination of marker and antibody or antibody fragment can be implemented by methods known in the art.Such as fluorescence mark
Remember protein process, biotin labeling method, alkali phosphatase enzyme mark method, peroxidase labelling method, phycobniliprotein labelling method, coral
Algae phycoerythrin labelling method etc..
It is not particularly limited as the sample according to testing product of the invention in the case where being suitable for measurement of the invention, including
Subject's biopsy heart tissue sample, blood plasma, blood, serum, lymph, urine, serous cavity liquid, spinal fluid, synovia, aqueous humor,
Tear, saliva or other treated specimen materials.
In specific embodiments of the present invention, the sample is organized from subject.
Purposes the present invention also provides HMGCL gene or HMGCL albumen as drug target in LVNC treatment.
Further, the drug includes the substance for promoting HMGCL gene expression and HMGCL protein expression.
Further, the substance for promoting HMGCL gene expression can promote HMGCL genetic transcription, enhancing HMGCL mRNA
Stability, activation HMGCL mRNA function etc..The substance of the activation HMGCL albumen can promote HMGCL gene translation, enhancing
HMGCL protein stability, HMGCL protein function etc..
The present invention also provides a kind of pharmaceutical composition that can be used for treating LVNC, the composition includes recited above
The agonist of HMGCL gene and/or HMGCL protein expressioning product.
Further, pharmaceutical composition of the invention further includes pharmaceutical carrier and pharmaceutical addition object.
Further, pharmaceutical composition of the invention includes micro-capsule, microballoon, nanoparticle, liposome, agar glycan globule etc.；
Pharmaceutical addition object include excipient, binder, diluent, thickener, filler, bonding agent, disintegrating agent, lubricant, grease or
It is non-grease base, surfactant, cosolvent, emulsifier, suspending agent, gelling agent, adjuvant, preservative, antioxidant, steady
Determine agent, colorant etc..Pharmaceutical composition of the invention includes the substance and above-mentioned medicine for promoting HMGCL gene and HMGCL protein expression
Mixing more than one or both of compositions.
Pharmaceutical composition of the invention can be used for treating the medicament of LVNC.
Pharmaceutical composition first choice of the invention is applied to mammal, and wherein mammal is preferably human patients.
Pharmaceutical composition of the invention the modes such as can take orally, inject and giving to human patients body.
Pharmaceutical composition of the invention can also be with the drug combination of other treatment cardiomyopathy.
The advantages of the present invention:
Present invention firstly discovers that HMGCL gene expresses significant decrease in LVNC, pass through detection subject cardiac muscular tissue
In HMGCL expression, can determine whether subject whether there is with LVNC risk, mentioned so that clinician be instructed to give subject
For prevention scheme or therapeutic scheme.
Detailed description of the invention:
Fig. 1 is to detect HMGCL in Non-compaction type cardiomyopathy (LVNC) and the normal heart using mass spectrometry method in embodiment
The expression of muscular tissue (NC) mixing sample；
Fig. 2 be in sharp embodiment with mass spectrometry method detect HMGCL single Non-compaction type cardiomyopathy (LVNC) with just
The expression of normal cardiac muscular tissue single sample；
Fig. 3 is the ROC song that embodiment Rabbit Myocardium HMGCL protein expression level diagnoses Non-compaction type cardiomyopathy
Line.
Specific embodiment
Heart lung preparation source used herein: 7 are suffered from LVNC and 7 donor hearts due to not row transplanting.All trouble
Person is signed with Written informed consent, and has been subjected to the agreement of Fu Wai Hospital, Chinese Academy of Medical Sciences ethics academic board.
Below in conjunction with drawings and examples, the present invention is described in further detail.Actual conditions are not specified in embodiment
Experimental method, carry out usually according to conventional conditions or according to the manufacturer's recommendations.
1 cardiac muscular tissue's sample of embodiment
Test population: study subject from Fu Wai Hospital, Chinese Academy of Medical Sciences carries out the patient of heart transplant and Yin tested
Cardiac size mismatches reason and not can be carried out the normal cardiac tissue sample of heart transplant between person and donor.
The diagnostic criteria of LVNC: LVNC still lacks unified internationally recognized diagnostic criteria at present, LVNC in the present invention
Diagnostic criteria is using current domestic just using more Jenni diagnostic criteria, including nonjoinder congenital heart disease；It is double-deck
Myocardial structural, internal layer are respectively that un-densified layer cardiac muscle and compacted zone are myocardium with outer layer, the un-densified layer of paradoxical expansion and compacted zone
Ratio is greater than 2；Position of disease is common in side wall, the apex of the heart and outer wall；Color Doppler ultrasound shows the girder crypts got deeply stuck in by blood
Infusate flow.
2 cardiac muscular tissue's holoprotein of embodiment extracts
2.1 cardiac muscular tissue's albumen sample extractions
Sample takes out from -80 DEG C, weighs appropriate tissue sample into the mortar of Liquid nitrogen precooler, liquid feeding nitrogen is fully ground to powder
End.Each group sample is separately added into 4 times of volume lysis buffers of powder (8M urea, 1% protease inhibitors and 2mM EDTA), surpasses
Sound cracking.4 DEG C, 12000g is centrifuged 10min, removes cell fragment, and supernatant is transferred to new centrifuge tube.
2.2 BCA method concentration mensurations
It indicates quantitatively to divide the protein concentration of cardiac muscular tissue's sample to specifications using BCA kit (Thermo)
Analysis.
Embodiment 3 mixes the expression in cardiac muscular tissue in Non-compaction type cardiomyopathy by mass spectral analysis HMGCL albumen
It is respectively 1 sample, 7 normal myocardium tissues by 7 LVNC cardiac muscular tissue albumen sample mixed in equal amounts of extraction
Albumen sample mixed in equal amounts is 1 sample.
3.1 pancreatin enzymatic hydrolysis
Dithiothreitol (DTT) is added in albumen sample solution makes its final concentration of 5mM, 56 DEG C of reduction 30min.Iodine is added later
Make its final concentration of 11mM for acetamide, room temperature, which is protected from light, is incubated for 15min.Finally the urea concentration of sample is diluted to lower than 2M.
Pancreatin is added with 1: 50 mass ratio (pancreatin: albumen), 37 DEG C of enzymatic hydrolysis are overnight.Again with 1: 100 mass ratio (pancreatin: egg
It is white) pancreatin is added, continue to digest 4h.
3.2 TMT label
The peptide fragment of pancreatin enzymatic hydrolysis vacuum freeze drying after desalination.Peptide fragment is dissolved with 0.5M TEAB, according to TMT kit
Operating instruction marks peptide fragment.Shirtsleeve operation is as follows: labelled reagent is dissolved after thawing with acetonitrile, is incubated at room temperature after mixing with peptide fragment
2h, desalination after the peptide fragment mixing after label, vacuum freeze drying.
3.3 HPLC classification
Peptide fragment is classified with high pH reverse hplc, and chromatographic column is Agilent 300Extend C18 (5 μm of partial sizes, in 4.6mm
Diameter, 250mm long).Operate it is as follows: peptide fragment stepwise gradient be 8%-32% acetonitrile, pH 9,60 components of 60min temporal separation, with
Peptide fragment merges into 9 components afterwards, carries out subsequent operation after the group lease making vacuum freeze drying after merging.
3.4 liquid chromatography-mass spectrometries (LC-MS)
Chromatographic condition: peptide fragment uses superelevation after being dissolved with liquid chromatogram mobile phase A phase (0.1% (v/v) aqueous formic acid)
Effect liquid phase systems are separated.Mobile phase A is the aqueous solution containing 0.1% formic acid and 2% acetonitrile；Mobile phase B is containing 0.1% formic acid
With the aqueous solution of 90% acetonitrile.Liquid phase gradient setting: 0~60min, 7%-25%B；60~82min, 25%-35%B；82-
86min, 35%-80%B；86~90min, 80%B, flow velocity maintain 700nL/min.
Mass Spectrometry Conditions: then peptide fragment is carried out ionizing in injection ion source after separating via ultra high efficiency liquid phase systems carries out matter
Spectrum analysis.Ion source voltage is set as 2.0kV, and peptide fragment parent ion and its secondary fragment are all carried out using high-resolution Orbitrap
Detection and analysis.First mass spectrometric scanning range is set as 350-1600m/z, and scanning resolution is set as 60,000；Second order ms
It is 100m/z that scanning range, which then fixes starting point, and second level scanning resolution is set as 30,000.Data acquisition scheme using data according to
Type is relied to scan (DDA) program, i.e., the highest preceding 20 peptide fragment parent ion of selection signal intensity sequentially enters HCD and touches after level-one scanning
It hits pond and carries out fragmentation using 28% fragmentation energies, equally successively carry out second mass analysis.In order to improve mass spectrographic effective benefit
With rate, automatic growth control (AGC) is set as 1E4, and signal threshold value is set as 33000ions/s, and maximum injection length is set as
The dynamic exclusion time of 60ms, tandem mass spectrum scanning are set as the multiple scanning for avoiding parent ion in 30 seconds.
Embodiment 4 passes through expression of the mass spectral analysis HMGCL albumen in the single cardiac muscular tissue of Non-compaction type cardiomyopathy
7 LVNC cardiac muscular tissue albumen after extraction no longer carry out equal proportion mixing and 7 normal myocardium histones
Also equal proportion mixing is no longer carried out, 14 tissue samples carry out pancreatin enzymatic hydrolysis, TMT mark respectively in next experimental implementation
Note, HPLC classification, liquid chromatography-mass spectrometry etc..
4.1 pancreatin enzymatic hydrolysis
Dithiothreitol (DTT) is added in albumen sample solution makes its final concentration of 5mM, 56 DEG C of reduction 30min.Iodine is added later
Make its final concentration of 11mM for acetamide, room temperature, which is protected from light, is incubated for 15min.Finally the urea concentration of sample is diluted to lower than 2M.
Pancreatin is added with 1: 50 mass ratio (pancreatin: albumen), 37 DEG C of enzymatic hydrolysis are overnight.Again with 1: 100 mass ratio (pancreatin: egg
It is white) pancreatin is added, continue to digest 4h.
4.2 TMT label
The peptide fragment of pancreatin enzymatic hydrolysis vacuum freeze drying after desalination.Peptide fragment is dissolved with 0.5M TEAB, according to TMT kit
Operating instruction marks peptide fragment.Shirtsleeve operation is as follows: labelled reagent is dissolved after thawing with acetonitrile, is incubated at room temperature after mixing with peptide fragment
2h, desalination after the peptide fragment mixing after label, vacuum freeze drying.
4.3 HPLC classification
Peptide fragment is classified with high pH reverse hplc, and chromatographic column is Agilent 300Extend C18 (5 μm of partial sizes, in 4.6mm
Diameter, 250mm long).Operate it is as follows: peptide fragment stepwise gradient be 8%-32% acetonitrile, pH 9,60 components of 60min temporal separation, with
Peptide fragment merges into 9 components afterwards, carries out subsequent operation after the group lease making vacuum freeze drying after merging.
4.4 liquid chromatography-mass spectrometries (LC-MS)
Mobile phase A is the aqueous solution containing 0.1% formic acid and 2% acetonitrile；Mobile phase B is containing 0.1% formic acid and 90% acetonitrile
Aqueous solution.Liquid phase gradient setting: 0~60min, 7%-25%B；60~82min, 25%-35%B；82-86min, 35%-
80%B；86~90min, 80%B, flow velocity maintain 700nL/min.
Mass Spectrometry Conditions: then peptide fragment is carried out ionizing in injection ion source after separating via ultra high efficiency liquid phase systems carries out matter
Spectrum analysis.Ion source voltage is set as 2.0kV, and peptide fragment parent ion and its secondary fragment are all carried out using high-resolution Orbitrap
Detection and analysis.First mass spectrometric scanning range is set as 350-1600m/z, and scanning resolution is set as 60,000；Second order ms
It is 100m/z that scanning range, which then fixes starting point, and second level scanning resolution is set as 30,000.Data acquisition scheme using data according to
Type is relied to scan (DDA) program, i.e., the highest preceding 20 peptide fragment parent ion of selection signal intensity sequentially enters HCD and touches after level-one scanning
It hits pond and carries out fragmentation using 28% fragmentation energies, equally successively carry out second mass analysis.In order to improve mass spectrographic effective benefit
With rate, automatic growth control (AGC) is set as 1E4, and signal threshold value is set as 33000ions/s, and maximum injection length is set as
The dynamic exclusion time of 60ms, tandem mass spectrum scanning are set as the multiple scanning for avoiding parent ion in 30 seconds.
4.5 statistical procedures
Using LC-MS's as a result, obtaining HMGCL in Non-compaction type cardiomyopathy (LVNC) and normal myocardium tissue (NC)
Expression in mixed protein sample and single albumen sample, using image analysis software to HMGCL in Non-compaction type
Cardiomyopathy (LVNC) and the difference of normal myocardium tissue (NC) expression quantity are analyzed, and have carried out the diagnosis of HMGCL expression
The ROC curve of LVNC is analyzed.
As shown in Fig. 1, in mixing cardiac muscular tissue's sample, HMGCL protein expression level is in LVNC patient cardiac muscular tissue
In be lower than normal myocardium tissue.
As shown in Fig. 2, in single cardiac muscular tissue's sample, HMGCL protein expression level is in LVNC patient cardiac muscular tissue
In be significantly lower than normal myocardium tissue, difference is extremely significant.* P < 0.05 is represented, for there were significant differences, it is pole that * *, which represents P < 0.01,
Significant difference, * * * represent P < 0.001.
As shown in Fig. 3, HMGCL diagnose LVNC ROC curve, reacted HMGCL as diagnosis LVNC sensibility with
The overall target of specificity.1- specificity is X-axis, and sensibility is Y-axis, and area under the curve (AUC) is 0.92, is greater than 0.7, explanation
HGCML has preferable diagnostic.
Claims (9)
1.HMGCL is as preparing the application of diagnostic tool and therapy target in the product of Non-compaction type cardiomyopathy.
2. diagnostic tool according to claim 1, which is characterized in that the product of the expression of detection HMGCL albumen.
3. product according to claim 2 includes can be in conjunction with the substance of HMGCL albumen.
4. substance is able to detect the expression of HMGCL albumen according to claim 3.
5. therapy target according to claim 1, which is characterized in that in conjunction with HMGCL gene or the product of HMGCL albumen.
6. product according to claim 5 includes the substance that can be combined HMGCL gene or can combine HMGCL albumen.
The agonist of 7.HMGCL gene and/or its expression product answering in preparation treatment Non-compaction type cardiac muscle medicine
With.
8. application according to claim 7, which is characterized in that the agonist include promote HMGCL gene expression and/or
Promote the substance of HMGCL protein expression.
9. a kind of for treating the pharmaceutical composition of Non-compaction type cardiomyopathy, which is characterized in that the pharmaceutical composition includes
Agonist described in claim 7 or 8.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890381A (en) * | 2003-09-24 | 2007-01-03 | 肿瘤疗法科学股份有限公司 | Method of diagnosing breast cancer |
| US20140322705A1 (en) * | 2010-08-20 | 2014-10-30 | Thomas Jefferson University | Cancer diagnostic and cancer therapeutic |
-
2018
- 2018-10-31 CN CN201811327907.3A patent/CN109234384A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890381A (en) * | 2003-09-24 | 2007-01-03 | 肿瘤疗法科学股份有限公司 | Method of diagnosing breast cancer |
| US20090286856A1 (en) * | 2003-09-24 | 2009-11-19 | Oncotherapy Science, Inc. | Method of Diagnosing Breast Cancer |
| US20140322705A1 (en) * | 2010-08-20 | 2014-10-30 | Thomas Jefferson University | Cancer diagnostic and cancer therapeutic |
Non-Patent Citations (1)
| Title |
|---|
| TÜLIN KÖKSAL等: "3-HMG Coenzyme A Lyase Deficiency: Macrocephaly and Left Ventricular Noncompaction with a Novel Mutation", 《INDIAN JOURNAL OF PEDIATRICS》 * |
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Application publication date: 20190118 |