CN113433324B - Application of Nck1 protein as marker in diagnosis of spinal cord injury - Google Patents
Application of Nck1 protein as marker in diagnosis of spinal cord injury Download PDFInfo
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- CN113433324B CN113433324B CN202110590700.0A CN202110590700A CN113433324B CN 113433324 B CN113433324 B CN 113433324B CN 202110590700 A CN202110590700 A CN 202110590700A CN 113433324 B CN113433324 B CN 113433324B
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses application of Nck1 protein as a marker in diagnosis of spinal cord injury, and belongs to the technical field of medicine. According to the invention, through research, nck1 protein is selectively expressed on cytoplasm and cell membrane of spinal cord neuron, and spinal cord injury can cause significant change of the protein expression level; meanwhile, the Nck1 protein is also found to regulate the proliferation of neurons and the growth and development of processes, so as to promote the regeneration and repair of neurons. Thus, the Nck1 protein can be used as a marker for diagnosing spinal cord injury. The invention provides a certain theoretical support for the clinical treatment of spinal cord injury.
Description
Technical Field
The invention belongs to the technical field of medicine, and particularly relates to application of Nck1 protein as a marker in diagnosis of spinal cord injury.
Background
Spinal Cord Injury (SCI) is a severe central nervous system injury that severely affects the quality of life of patients with serious socioeconomic consequences. In SCI, primary injury causes tension, compression and shear forces on the spinal cord, which can damage the central and peripheral nervous systems. In addition, secondary SCI effects, including edema, ischemia, apoptosis, inflammation, and electrolyte imbalance, can lead to further injury, all of which can lead to serious neurological deficits, such as cognitive and behavioral impairment. Currently, a series of methods, including nerve growth factor and cell implantation, can create a suitable environment for neuron survival and axon regeneration, preventing further development of SCI injury. However, the identification of effective molecular targets is a difficult task and the underlying molecular mechanisms of SCI impairment remain to be explored further.
Nck1 consists of one SH2 domain and three SH3 domains, and Nck1 acts as a scaffold protein that binds surface receptors to the SH2 domain and then transmits a signal to downstream molecules via the SH3 domain. It was reported that more than 60 proteins could bind to Nck1 and interact. Nck1 regulates a variety of cellular processes including DNA synthesis, translation, protein degradation, and actin cytoskeletal reorganization. Many studies have shown that Nck1 is highly expressed in tumor tissues and is involved in the activation of extracellular signal-regulated kinase (ERK). Furthermore, nck1 is expressed in the developing nervous system, including in the embryonic and early postnatal forebrain, and plays a role in neuronal growth cones; nck1 can also recognize specific extracellular signals and transmit them to the neuron body to induce axonal movement. However, very little research has been conducted into the expression and function of Nck1 in spinal cord tissue, and the underlying molecular mechanism of Nck1 after SCI.
Disclosure of Invention
The aim of the present invention is to study the spinal localization and expression changes of the Nck1 protein after Spinal Cord Injury (SCI), observe its endogenous role in the pathological development of SCI, and investigate its possible underlying molecular mechanisms.
In order to achieve the above object, the present invention adopts the following technical means:
application of a substance for detecting Nck1 protein in preparing a spinal cord injury diagnostic reagent.
Further, the substance for detecting the Nck1 protein is a substance for detecting the expression amount of the Nck1 protein and/or a substance for detecting the concentration of the Nck1 protein.
A diagnostic reagent for diagnosing or aiding in the diagnosis of spinal cord injury, comprising a substance for detecting Nck1 protein.
Application of Nck1 protein as a marker in development of a spinal cord injury diagnostic reagent.
Application of Nck1 protein as a marker in the development of a drug for treating spinal cord injury.
The amino acid sequence of the Nck1 protein (GeneID number: 300955) is shown IN SEQ IN NO. 1.
Has the advantages that: according to the invention, through research, nck1 protein is selectively expressed on cytoplasm and cell membrane of spinal cord neuron, and spinal cord injury can cause significant change of the protein expression level; meanwhile, the Nck1 protein is also found to regulate the proliferation of neurons and the growth and development of processes, so as to promote the regeneration and repair of neurons. The invention discloses that Nck1 protein may have important biological functions in SCI development, and provides certain theoretical support for clinical spinal cord injury treatment.
Drawings
FIG. 1 shows the results of SCI model construction. A is behavioral change after behavioral testing of rats spinal cord injury (n = 25); b is LFB staining of spinal cord.
Fig. 2 shows the results of changes in expression of Nck1 after spinal cord injury. A is the expression of Nck1 after spinal cord injury detected by qRT-PCR method, and compared with the sham operation group; b is a western blot analysis of rat spinal cords at different times post-surgery, with representative bands labeled Nck1 and GAPDH shown above and the ratio of Nck1 to GAPDH shown below (.;. Times.P < 0.05;. Times.P < 0.01).
Fig. 3 shows the results of immunofluorescence staining of spinal cord Nck 1. A indicates that the Nck 1-positive cells have large and round nuclei (nuclei were labeled with DAPI; B indicates that Nck 1-positive signals were observed in both cytoplasm and membrane; scale: 20 μm.
Fig. 4 is the results of immunofluorescence staining for Nck1 for different neuron-specific markers, where: nck1 is shown in red; neuron-specific markers are shown in green and include NeuN, NF-200, and NF-M; the scale is 20 μm.
FIG. 5 shows immunofluorescence staining of Nck1 at various time points after SCI. Wherein: rat spinal cord sections were probed with Nck1 (red) and neurons were labeled with NeuN (green). Nck1 was observed in plasma and membrane of neurons at day 7, and Nck 1-positive neurons were morphologically normal.
FIG. 6 is the result of transfection of VSC4.1 cells with Nck 1-specific siRNA. A is decreased expression of Nck1 in Nck1-siRNA treated VSC4.1 cells compared to control; b is obvious inhibition of neuron length in VSC4.1 cells after Nck1-siRNA transfection; c is cell viability of VSC4.1 cells treated with Nck1-siRNA and compared to control group (. P < 0.05); d is the calculated protrusion length of Nck1-siRNA treated VSC4.1 cells and compared to control group (. P < 0.05;. P < 0.01).
Detailed Description
The technical solution of the present invention is explained in detail below. The following examples are intended to facilitate a better understanding of the invention, but are not intended to limit the invention thereto. The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1
The experimental procedure of this implementation was as follows:
1. SCI model construction
25 female Sprague Dawley rats weighing 200 to 220g were randomized into SCI (n = 20) and sham (n = 5) groups. Under anesthesia, a dorsal laminectomy was performed to expose the dorsal tissue between the T8 and T10 thoracic vertebrae. In the T9 zone, a 2.0 mm tip dropped a force of 1.5N (Precision Systems & Instrumentation, fairfax Station, VA, USA). Sham operated animals were only anesthetized and underwent laminectomy without comparative injury. All surgical interventions and post-operative animal care were in accordance with the national institutes of health (USA) laboratory animal care and use guidelines (NIH Publication No. 85-23, reviewed 1996). The study was approved by ethics committee of ethics for laboratory animals in Jiangsu province (apreval No. 2019-0306-001).
2. Behavioral analysis
The recovery of rat function was tested using Basso, beattie, bresnahan (BBB) system with a score range of 0 to 21. Under blind conditions, rats were treated in a round, open space and allowed free walking. Trunk stability, knee joint coordination and paw range of motion were evaluated once within 4 minutes by two observers for each rat. The mean score was calculated and taken as the mean ± standard error.
3. Luxol Fast Blue (LFB) staining
After anesthetizing the rats, they were perfused with physiological saline and 4% paraformaldehyde, and the spinal cords were excised and cut into 10 μm sections. Frozen sections were stained overnight at 58 ℃ in LFB mix (0.1% LFB with 95% ethanol and 0.05% acetic acid). Next, the slices were rinsed in 95% EtOH, then 75% ethanol, and finally rinsed completely in distilled water and then dipped in 0.05% Li 2 CO 3 Further differentiation was stopped. Finally, the sections were rinsed with 75% ethanol, 95% and 99% ethanol, respectively, until white myelin tissue appeared.
4. Immunofluorescent staining
After anesthesia and perfusion in rats, spinal cords were excised and cut into 10 μm sections. All samples were blocked with 0.1% TritonX-100 in 3% Bovine Serum Albumin (BSA) for 30 min at room temperature. First, the primary antibody was diluted in 3-vol bsa, and then the sections were incubated with this solution overnight at 4 ℃. anti-Nck 1 antibody (rabbitt, 1, 1000, abcam, cambridge, UK) was used simultaneously with the neural markers NeuN (1. The following day, after three washes in Phosphate Buffered Saline (PBS), sections were incubated with secondary antibodies for 2 hours at room temperature, three washes in PBS, and then sections were stained with nuclear stain 4', 6-diamino-2-phenylindole (DAPI; vector Laboratories, burlingame, calif., USA). All images were observed with a fluorescence microscope (Leica microsystems, wetzlar, germany). .
5. Cell culture
VSC4.1 cells were established by mixing rat ventral spinal cord neurons with mouse N18TG2 neuroblastoma cells. Cells were at 37 ℃ and 95% O 2 And 5% CO 2 A humidified incubator.
6. Immunoblotting
The pseudospinal cord was excised or the spinal cord was injured, and 10mm around the center of the injury was excised. The samples were hand minced, homogenized in immunoprecipitation buffer (1% sodium dodecyl sulfate, 1% NP-40, 50mTris base and 1m M phenylmethylsulfonyl fluoride) for 30 minutes, and then centrifuged at 12000rpm for 15 minutes at 4 ℃. The supernatant was collected and transferred to a new microtube, and then the protein concentration was determined by the dioctanoate method. The lysates were separated by electrophoresis on a 12% sodium dodecyl sulfate polyacrylamide gel and then transferred to a polyvinyl fluoride membrane. After three washes with Tris buffered saline, membranes were blocked with 5% skim milk for 2 hours at room temperature. After blocking, the membrane was incubated overnight at 4 ℃ with primary antibodies against Nck1 (rabbit, 1:2, 000 Abcam) and GAPDH (rabbit, 1:5, 000; sigma-Aldrich, st Louis, MO, USA). The next day, incubation with horseradish peroxidase secondary antibody was 2 hours. Protein bands were then visualized by enhanced chemiluminescence and using imaging laboratory @ 5.1 software (Bio-Rad Laboratories Inc., hercules, calif., USA).
7. RNA extraction and real-time quantitative polymerase chain reaction (qRT-PCR)
Total RNA was extracted from spinal cord tissue or VSC4.1 cells according to the instructions (QIAGEN, chatsworth, CA, USA). Next, the RNA was reverse transcribed to cDNA for qRT-PCR (ThermoFisher science, waltham, MA, USA). The following primers were used:
GAPDH: forward 5'-GAGGTAGTATGGCGTAGTGC-3' (SEQ IN NO. 2)
Reverse 5'-CTGGTTTCTGGAGATGGG-3' (SEQ IN NO. 3)
Nck1: forward 5'-GCTCGGAAAGCATCTT-3' (SEQ IN NO. 4)
Reverse 5'-TACATGGTCACCAAGG-3' (SEQ IN NO. 5).
With GAPDH as internal reference, use 2 –△△CT The method analyzes the result.
8. Cell count kit-8 (CCK-8) assay
VSC4.1 cells were transfected with control or Nck1siRNA and then cell viability was determined using CCK-8 (Beyotime Biotechnology, shanghai, china) according to the manufacturer's instructions. All cell viability assays were performed in triplicate.
The results are as follows:
1. behavioral changes in rats following spinal cord injury
To ensure successful construction of the SCI animal model, the recovery of spontaneous motor function in rats after SCI was assessed using the BBB scoring system, as shown in figure 1A. After injury, SCI rats had almost complete loss of hind limb movement compared to sham surgery with a BBB score of 0. The blood brain barrier score was low, with slight recovery until 7 days post injury, and SCI rats recovered much less than the sham group, although spontaneous functional improvement appeared in the following days. These results indicate that the SCI animal model is successfully established.
2. Spinal cord morphological changes following spinal cord injury
Morphological changes in spinal cord after spinal cord injury were detected by LFB staining. Normal spinal cord is in intact structure with obvious gray matter, white matter and myelin sheath. After injury, the integrity of the spinal cord is destroyed, the nerve conduction tracts are blocked, and SCI rats have extensive cell death and demyelination. There are numerous vacuoles and irregular spaces around the center of the lesion, axonal degradation, and cell disorders, as shown in FIG. 1B.
3. Temporal expression analysis of Nck1 after spinal cord injury
To investigate the role of Nck1 in the SCI process, its expression at different time points was analyzed using qRT-PCR and western blot. The qRT-PCR results showed that Nck1 expression decreased to a minimum level 1 day after SCI, followed by a gradual increase over several days, as shown in fig. 2A. The immunoblot assay showed the same results, as shown in fig. 2B. Nck1 dropped to a low level 1 day after SCI and then slowly increased to a stable level 35 days after SCI, although this level was still lower than in the sham group, as shown in fig. 2B. These results indicate that Nck1 may be involved in the pathological process of SCI in a time-dependent manner.
4. Localization and expression changes of Nck1 after spinal cord injury
Immunocytochemistry was used to differentiate the cellular localization of Nck1 in spinal cord tissue. Nck1 is mainly expressed in cells with large nuclei, which have similar morphological features to neurons, as shown in fig. 3A. In addition, an Nck1 positive signal was also observed on the cell membrane, as shown in FIG. 3B. To test whether Nck 1-positive cells are neurons, the present invention co-labeled sections with neuron-specific markers NeuN, NF-200, and NF-M, as shown in FIG. 4. In fact, nck1 was selectively distributed in gray matter neurons, whereas no Nck1 staining was observed in astrocytes or any other cells.
To further examine the change in Nck1 expression after injury, spinal cord tissues at different time points in the SCI model were selected for immunofluorescence experiments. 1 day after SCI, many neurons expressing Nck1 were apoptotic and morphologically atrophied; compared to the sham group, nck1 began to appear in the plasma and membranes of normal morphology neurons 7 days after SCI, as shown in fig. 5.
5. Change in VSC4.1 cell process growth to reduce Nck1
Nck1 has been reported to regulate neuronal differentiation and development. To investigate whether Nck1 is involved in neuronal development, the present invention used Nck1-siRNA to find the best silencing effect, and three Nck 1-siRNAs (si 1, si2 and si 3) were transfected into VSC4.1 cells, respectively.
The three siRNA sequences are as follows:
si1
forward5'-GACCAUGUAGGUUCUCUGUDTDT-3'(SEQ IN NO.6)
reverse 5'-ACAGAGAACCUACAUGGUCDTDT-3'(SEQ IN NO.7)
si2
forward5'-CAAAAAGGCACCGAUCUUUDTDT-3'(SEQ IN NO.8)
reverse 5'-AAAGAUCGGUGCCUUUUUGDTDT-3'(SEQ IN NO.9)
si3
forward5'-GGACACCUUAGGCAUUGGADTDT-3'(SEQ IN NO.10)
reverse5'-UCCAAUGCCUAAGGUGUCCDTDT-3'(SEQ IN NO.11)
RT-PCR results showed that of the three siRNAs, the magnitude of reduction of Nck1 was greatest in si3 transfected cells compared to negative control cells, as shown in FIG. 6A. Therefore, si3 was used in subsequent experiments.
To determine whether Nck1 is involved in neuronal proliferation, VSC4.1 cells were transfected with control and Nck1-siRNA, and then cell proliferation and viability were analyzed with CCK8, with a significant reduction in viability of si3 transfected cells compared to the control group, as shown in figure 6B. This result indicates that Nck1 is involved in regulating the proliferation of VSC4.1 cells. In addition, the protrusion length of Nck1-siRNA transfected cells was significantly shorter than that of control cells, as shown in FIGS. 6C and 6D. These results clearly show that a decrease in Nck1 can lead to inhibition of VSC4.1 cell proliferation and outgrowth.
Sequence listing
<110> university of southeast Tong
Application of <120> Nck1 protein as marker in diagnosis of spinal cord injury
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Claims (1)
1. A diagnostic reagent for diagnosing or aiding in the diagnosis of spinal cord injury, comprising: including substances for detecting Nck1 protein;
the substance for detecting the Nck1 protein is a substance for detecting the expression amount of the Nck1 protein;
the substance for detecting the expression level of the Nck1 protein comprises a primer pair combination consisting of a specific primer pair and an internal reference primer pair;
the specific primer pairs are as follows:
forward direction 5'-GCTCGGAAAGCATCTT-3'
Reverse direction 5'-TACATGGTCACCAAGG-3';
the reference primer pair is as follows:
forward direction 5'-GAGGTAGTATGGCGTAGTGC-3'
Reverse direction 5'-CTGGTTTCTGGAGATGGG-3'.
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