CN103278624A - Marker molecule CHL1 for low oxygen, and application thereof - Google Patents
Marker molecule CHL1 for low oxygen, and application thereof Download PDFInfo
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Abstract
The invention discloses a marker molecule CHL1 for low oxygen, and an application thereof, and belongs to the technical field of biomedical materials. The marker molecule is a cell adhesion molecule CHLl, and the protein sequence of the marker molecule is shown as SEQ ID No. 1 or SEQ ID No. 2. The CHL1 can be used as the marker molecule for the low oxygen. An antibody and an enzyme-labeled second antibody which are prepared by the marker molecule by an immunological method can detect whether an animal or person is in the low oxygen state or not by using an enzyme-linked immunoassay method, with reliable detection sensitivity.
Description
Technical field
The invention belongs to technical field of biomedical materials, be specifically related to a kind of hypoxemia marker molecule CHL1 and application thereof.
Background technology
The environment hypoxia injury is the common problem that ambits such as plateau medicine, aerospace medicine, sports medical science face all the time, also is the key areas of special environmental physiology research
[1,2]Hypoxemia can cause the main systemic-function obstacle of nerve, breathing and circulation, can cause respiratory failure, threat to life when serious
[3]Hypoxemia also is the total pathophysiological processes of cardiovascular and cerebrovascular diseases such as numerous disease such as myocardium infarct, cerebral infarction, atherosclerotic, in addition, hypoxemia also is one of key character of solid tumor microenvironment, is that solid tumor produces the major reason of tolerance and prognosis weak effect to radiotherapy, chemotherapy clinically
[4]Therefore, hypoxemia is the important pathophysiological factor that is detrimental to health.
Cell adhesion molecule (cell adhesion molecules, CAMs) be the microenvironment of cells in vivo existence, can promote between cell and the cell, adhere between cell and the extracellular matrix and identification, playing an important role in keeping eucaryotic cell structure complete sum cell signalling, is the important regulating and controlling factor of cell growth and nervous system development process.CAMs mainly is divided into four classes: integrin family, immunoglobulin superfamily, the plain family of selection and cadherin family
[5](close homologue of L1 CHL1), claims CALL, L1CAM2 again to CHL1, is that Holm in 1996 etc. clone in the mouse genome and obtain, and with the gene of nerve adhesion molecule L1 height homology, belongs to the member of adhesion molecule immunoglobulin superfamily.CHL1 is as a kind of transmembrane protein, comprises N end signal sequence, 6 immunoglobulin (Ig)s (Ig) spline structure territory, 5 fibronectin III (FnIII) repetitive sequence, a membrane spaning domain and contains the conservative intracellular region of skelemin ankyrin (anykrin) recognition sequence (FIGAY).Different with L1 is that CHL1 not only is expressed in the neuron in central nervous system, exists equally in spongiocyte
[6]Domestic and international research to CHL1 at present mainly concentrates in the nervous system, is a kind of short neuronal survival factor as CHL1
[7]In the central nervous system growth course, CHL1 comes off and discharges the formation that promotes aixs cylinder with soluble substrate combining form by ectodomain
[8]By combine the cell migration that CHL1 mediation integrin relies on extracellular matrix protein
[9]Central lesion can cause CHL1 high expressed in the neuron with regeneration axon function
[10]The pressure stress can cause mouse hippocampus CHL1 down-regulated expression
[11]Simultaneously, adhesion molecule CHL1 gene mutation be human schizophrenia main diseases because of
[12]
Along with progressively going deep into of CHL1 research, the related tool mouse is also arisen at the historic moment.2002, reported first such as M.Montag-Sallaz: obtain the CHL1 knock out mice by gene targeting and homologous recombination technique, and be used for experimental study.CHL1 gene delection mouse can survive and breed normally, but has certain defective in the growth of nervous process with aspect the learning and memory after growing up
[13]Studies show that: after the CHL1 gene delection, the projection of cortical neuron is inverted and is increased, and the study of mouse and cognitive behavior are learned and be subjected to influence
[14]The report of adhesion molecule in injury repair also caused concern in recent years, Jakovcevski in 2007 etc. discover the mouse of CHL1 gene delection after the spinal cord injury, can form by the scar due to the inhibition spongiocyte, and the functional rehabilitation after the promotion spinal cord injury
[15]The inventor discovers: the expression of CHL1 in different brains district, the heart, lung, kidney significantly reduced under the different hypoxia conditions
[16]Prompting, cell adhesion molecule CHL1 may be used for clinical diagnosis as the marker molecule of hypoxia injury.
Summary of the invention
The object of the present invention is to provide a kind of hypoxemia marker molecule CHL1 and the application aspect preparation hypoxemia diagnostic kit thereof.
A kind of hypoxemia marker molecule, this marker molecule are CHL1, and its protein sequence is shown in SEQ ID No.1 or SEQ ID No.2.
The application of described hypoxemia marker molecule in preparation animal and people's hypoxemia detection kit.
Described animal is mouse.
Described kit comprises ELISA Plate, CHL1 antibody, ELIAS secondary antibody, and enzyme linked immunoassay reagent commonly used.
Enzyme in the described ELIAS secondary antibody is horseradish peroxidase.
Beneficial effect of the present invention: cell adhesion molecule CHL1 of the present invention can be used as a kind of hypoxemia marker molecule, the applied immunology method, utilize antibody and the ELIAS secondary antibody of this marker molecules preparation, utilize enzyme linked immunological to learn detection method, can detect animal and people and whether be in hypoxia, detect sensitive reliable.
Description of drawings
Fig. 1 handles behind the 24h result of CHL1 content in the mice plasma for ELISA detects acute hypoxia.
Fig. 2 detects behind Chronic hypoxia 14d, the 28d result of CHL1 content in the mice plasma for ELISA.
Fig. 3 is the result of CHL1 content in the human plasma under ELISA detection height above sea level 3000m, the 4800m rice plateau hypoxemia.
Embodiment
The present invention will be further described below in conjunction with the drawings and specific embodiments.
Following examples material therefor PROTEIN C HL1, its protein sequence is shown in SEQ ID No.1 or SEQ ID No.2.
The experiment of embodiment 1 mouse hypoxemia
(1) acute hypoxia
The C57 mouse (being provided by Military Medical Science Institute's animal center) of 40 average weight 22～24g is divided into 2 groups, and 20 every group is respectively control group, acute hypoxia group.Animal used as test is (giving the 5000m hypobaric hypoxia) processing 24h in normal oxygen, hypoxemia cabin respectively.The hypoxemia cabin at the uniform velocity rises to 5000 meters with the speed of 20 meter per seconds, and experiment finishes the back and at the uniform velocity is down to normal oxygen with 20 meter per second speed.Pluck eyeball immediately after the hypoxemia processing finishes and get blood, be used for the detection of CHL1.
(2) Chronic hypoxia
The C57 mouse (being provided by Military Medical Science Institute's animal center) of 60 average weight 22～24g is divided into 3 groups, and 20 every group is respectively that control group, Chronic hypoxia 14 days groups, Chronic hypoxia were organized in 28 days.The experimental group animal gives 10%O at normal oxygen, hypoxemia in the cabin respectively
2Hypoxemia was handled 14 days, 28 days.The hypoxemia cabin is down to 10% with oxygen concentration in advance, and the same day was put into the hypoxemia cabin with mouse in experiment, takes out after 14 days, 28 days respectively, plucks eyeball immediately and gets blood, is used for the detection of CHL1.
(3) extraction of blood plasma
The blood of taking is put in the test tube that contains anti-coagulants (EDTAP dipotassium ethylene diamine tetraacetate), after the mixing, with the centrifugal 10min of 3000rpm, made it to separate with haemocyte, branch is got supernatant and is blood plasma.It is standby that blood plasma is kept at-80 degree.
(4) CHL1 content in the blood plasma that extracts of enzyme linked immunosorbent detection
Reagent:
1, carbonate coating buffer: 3.03g Na
2CO
3, 6.0g NaHCO
3, be dissolved in the 900ml distilled water, adjust pH to 9.6, be settled to 1L;
2, PBS:1.16g Na
2HPO
4, 0.1g KCl, 0.1g K
3PO
4, 4.0g NaCl is dissolved in 500mL distilled water, adjusts pH to 7.4;
3, confining liquid: be dissolved in the 1%BSA of PBS, 5% skim milk;
4, cleansing solution: TBST (Tris-HCl, pH7.4+0.05% polysorbas20);
5, antibody or antigenic dilution: 1 * confining liquid;
6, stop buffer: 2N H
2SO
4
Operation steps:
A, coated antibody: the CHL1 antibody of carbonate coating buffer dilution is added in the 96 hole ELISA Plate, and the CHL1 antibody concentration is 1 μ g/ml, and every hole 100 μ l cover the lamina membranacea bag and spent night by 4.
B, discard coating buffer with cleansing solution washing 2 times, pat orifice plate cleansing solution is dried.
C, sealing: add 200 μ l confining liquids (1%BSA or 5% skim milk etc.) room temperature sealing 1 hour in every hole.
D, every hole add 100 μ l and dilute good sample (2 μ l blood plasma+98 μ l dilutions), and 37 degree were hatched 60～90 minutes.
E, get rid of the solution of orifice plate the inside, cleansing solution washing 3 times, each 10 minutes.
F, every hole add the detection antibody (dilution in 1: 500) of 100 μ l, incubated at room 2 hours.
G, hatch back cleansing solution washing 4 times, each 10 minutes.
H, every hole add two anti-(1: 500) of the horseradish peroxidase-labeled of 100 μ l, continue incubated at room 1-2 hour.
I, hatch back cleansing solution washing four times.
J, every hole add the tmb substrate solution of 100 μ l, and waiting to develop the color fully, the back adds the stop buffer of 100 μ l and measures the 450nm absorbance in microplate reader.
Testing result as depicted in figs. 1 and 2, the 450nm absorbance of acute hypoxia mouse is 0.625, normal mouse be 0.278, both difference has reached difference extremely significantly, the absorbance of Chronic hypoxia 14 days and 18 days is respectively 0.398 and 0.425, reached the level of signifiance, illustrated that CHL1 can be used as the hypoxemia marker molecule, and can be according to the corresponding hypoxemia detection kit of this Experiment Preparation.
The experiment of embodiment 2 people's hypoxemia
(1) simulated high altitude hypoxemia: 10 volunteers of picked at random enter the hypoxemia cabin, and vein is got blood under normal oxygen, simulation height above sea level 3600m, height above sea level 4800m low-oxygen environment respectively, is used for the detection of CHL1.
(2) extraction of blood plasma
The blood of taking is put in the test tube that contains anti-coagulants (EDTAP dipotassium ethylene diamine tetraacetate), after the mixing, with the centrifugal 10min of 3000rpm, made it to separate with haemocyte, branch is got supernatant and is blood plasma.It is standby that blood plasma is kept at-80 degree.
(3) CH1 content in the blood plasma that extracts of enzyme linked immunosorbent detection
Reagent:
1, carbonate coating buffer: 3.03g Na
2CO
3, 6.0g NaHCO
3, be dissolved in the 900ml distilled water, adjust pH to 9.6, be settled to 1L;
2, PBS:1.16g Na
2HPO
4, 0.1g KCl, 0.1g K
3PO
4, 4.0g NaCl is dissolved in 500mL distilled water, adjusts pH to 7.4;
4, confining liquid: be dissolved in the 1%BSA of PBS, 5% skim milk;
4, cleansing solution: TBST (Tris-HCl, pH7.4+0.05% polysorbas20);
5, antibody or antigenic dilution: 1 * confining liquid;
6, stop buffer: 2N H
2SO
4
Operation steps:
A, coated antibody: the CHL1 antibody of carbonate coating buffer dilution is added in the 96 hole ELISA Plate, and the CHL1 antibody concentration is 1 μ g/ml, and every hole 100 μ l cover the lamina membranacea bag and spent night by 4.
B, discard coating buffer with cleansing solution washing 2 times, pat orifice plate cleansing solution is dried.
C, sealing: add 200 μ l confining liquids (1%BSA or 5% skim milk etc.) room temperature sealing 1 hour in every hole.
D, every hole add 100 μ l and dilute good sample (2 μ l blood plasma+98 μ l dilutions), and 37 degree were hatched 60～90 minutes.
E, get rid of the solution of orifice plate the inside, cleansing solution washing 3 times, each 10 minutes.
F, every hole add the detection antibody (dilution in 1: 500) of 100 μ l, incubated at room 2 hours.
G, hatch back cleansing solution washing 4 times, each 10 minutes.
H, every hole add two anti-(1: 500) of the horseradish peroxidase-labeled of 100 μ l, continue incubated at room 1-2 hour.
I, hatch back cleansing solution washing four times.
J, every hole add the tmb substrate solution of 100 μ l, and waiting to develop the color fully, the back adds the stop buffer of 100 μ l and measures the 450nm absorbance in microplate reader.
Testing result as shown in Figure 3, normal person 450nm absorbance is 0.255, the people's that simulation height above sea level 3600m hypoxemia is handled absorbance is 0.314, the people's that simulation height above sea level 4800m hypoxemia is handled absorbance is 0.356, illustrate that CHL1 can be used as the hypoxemia marker molecule, and can be according to the corresponding hypoxemia detection kit of this Experiment Preparation.
List of references
[1]Elangbam，C.S.，C.W.Qualls，Jr.，and?R.R.Dahlgren，Cell?adhesion?molecules--update.Vet?Pathol，1997.34(1)：p.61-73.
[2]Buckley，C.D.，et?al.，Cell?adhesion：more?than?just?glue.Mol?Membr?Biol，1998.15(4)：p.167-76.
[3]Gibson，N.J.，Cell?adhesion?molecules?in?context：CAM?function?depends?on?the?neighborhood.Cell?Adh?Migr，2011.5(1)：p.48-51.
[4]Burden-Gulley，S.M.，M.Pendergast，and?V.Lemmon，The?role?of?cell?adhesion?molecule?L1?in?axonal?extension，growth?cone?motility，and?signal?transduction.Cell?Tissue?Res，1997.290(2)：p.415-22.
[5]Holm，J.，et?al.，Structural?features?of?a?close?homologue?of?L1(CHL1)in?the?mouse：a?new?member?of?the?L1family?of?neural?recognition?molecules.Eur?J?Neurosci，1996.8(8)：p.1613-29.
[6]Chen，S.，et?al.，Prevention?of?neuronal?cell?death?by?neural?adhesion?molecules?L1?and?CHL1.J?Neurobiol，1999.38(3)：p.428-39.
[7]Hillenbrand，R.，et?al.，The?close?homologue?of?the?neural?adhesion?molecule?L1(CHL1)：patterns?of?expression?and?promotion?of?neurite?outgrowth?by?heterophilic?interactions.Eur?J?Neurosci，1999.11(3)：p.813-26.
[8]Buhusi，M.，et?al.，Close?homolog?of?L1?is?an?enhancer?of?integrin-mediated?cell?migration.J?Biol?Chem，2003.?278(27)：p.25024-31.
[9]Chaisuksunt，V.，et?al.，The?cell?recognition?molecule?CHL1?is?strongly?upregulated?by?injured?and?regenerating?thalomic?neurons.J?Comp?Neurol，2000.425(3)：p.382-92.
[10]Jakovcevski，I.，et?al.，Glial?scar?expression?of?CHL1，the?close?homolog?of?the?adhesion?molecule?L1，limits?recovery?after?spinal?cord?injury.J?Neurosci，2007.27(27)：p.7222-33.
[11]Desarnaud，F.，et?al.，Stress?downregulates?hippocampal?expression?of?the?adhesion?molecules?NCAM?and?CHL1?in?mice?by?mechanisms?independent?of?DNA?methylation?of?their?promoters.Cell?Adh?Migr，2008.2(1)：p.38-44.
[12]Sakurai，K.，et?al.，An?association?between?a?missense?polymorphism?in?the?close?homologue?of?L1(CHL1，CALL)gene?and?schizophrenia.Mol?Psychiatry，2002.7(4)：p.412-5.
[13]Montag-Sallaz，M.，M.Schachner，and?D.Montag，Misguided?axonal?projections，neural?cell?adhesion?molecule180mRNA?upregulation，and?altered?behavior?in?mice?deficient?for?the?close?homolog?of?L1.Mol?Cell?Biol，2002.22(22)：p.7967-81.
[14]Kolata，S.，et?al.，Impaired?working?memory?duration?but?normal?learning?abilities?found?in?mice?that?are?conditionally?deficient?in?the?close?homolog?of?L1.J?Neurosci，2008.28(50)：p.13505-10.
[15]Jakovcevski?I，et?al.(2007)Glial?scar?expression?of?CHL1，the?close?homolog?of?the?adhesion?molecule?L1，limits?recovery?after?spinal?cord?injury.J?Neurosci，2007.27(27)：p.7222-33.
[16] the bright acute hypoxia of the Sun Jia military model of yellow glad Zhu's tinkling of pieces of jades Wu Kui is organized influence China's applied physiology magazine the 3rd phase in 2011 of horizontal expression to mouse adhesion molecule CHL1.
Claims (5)
1. a hypoxemia marker molecule is characterized in that, this marker molecule is CHL1, and its protein sequence is shown in SEQ ID No.1 or SEQ ID No.2.
2. the application of the described hypoxemia marker molecule of claim 1 in preparation animal and people's hypoxemia detection kit.
3. according to the application of the described hypoxemia marker molecule of claim 2 in preparation animal and people's hypoxemia detection kit, it is characterized in that described animal is mouse.
4. an animal and people's hypoxemia diagnostic kit is characterized in that described kit comprises ELISA Plate, CHL1 antibody, ELIAS secondary antibody, and enzyme linked immunoassay reagent commonly used.
5. according to the described a kind of animal of claim 4 and people's hypoxemia diagnostic kit, it is characterized in that the enzyme in the described ELIAS secondary antibody is horseradish peroxidase.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2019190883A (en) * | 2018-04-19 | 2019-10-31 | 学校法人 埼玉医科大学 | New lung cancer marker |
| US11117962B2 (en) * | 2016-12-02 | 2021-09-14 | The University Of Tokyo | Antibody to fibrosis-related molecule and medical application thereof |
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| CN102268483A (en) * | 2011-08-10 | 2011-12-07 | 中国人民解放军军事医学科学院基础医学研究所 | Early hypoxia detection kit with miRNA-210 as marker |
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| CN102268483A (en) * | 2011-08-10 | 2011-12-07 | 中国人民解放军军事医学科学院基础医学研究所 | Early hypoxia detection kit with miRNA-210 as marker |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11117962B2 (en) * | 2016-12-02 | 2021-09-14 | The University Of Tokyo | Antibody to fibrosis-related molecule and medical application thereof |
| US11866497B2 (en) | 2016-12-02 | 2024-01-09 | The University Of Tokyo | Antibody to fibrosis-related molecule and medical application thereof |
| JP2019190883A (en) * | 2018-04-19 | 2019-10-31 | 学校法人 埼玉医科大学 | New lung cancer marker |
| JP7106810B2 (en) | 2018-04-19 | 2022-07-27 | 学校法人 埼玉医科大学 | Novel lung cancer marker |
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