KR20120085004A - Method for detecting radiation response genes in mice with gamma-radiation and the genes - Google Patents
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Abstract
Description
본 발명은 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법 및 면역유전자군에 관한 것으로, 보다 상세하게는 고선량률 및 저선량률 전리 방사선 조사된 AKR/J 마우스에서 공통적으로 발견되는 암 발병 조절 특이 면역유전자와 그 특이 면역유전자를 검출하는 방법에 관한 것이다.
The present invention relates to a method for detecting cancer-generating immunogenes and immunogene groups in ionizing irradiated mice, and more particularly, to cancer development commonly found in high-dose and low-dose ionizing irradiated AKR / J mice. The present invention relates to a regulatory specific immunogene and a method for detecting the specific immunogene.
일반적으로, 방사선과 암 발생과의 상관성, 특히 면역유전자 반응에 대한 연구가 수행되어 왔으나, 그 결과의 신뢰성을 저해하는 교란변수가 많이 개입되어 있었다. 이는 종래의 연구들이 대부분 암세포를 이용하거나 일반 마우스를 이용하였기 때문에 발현된 면역유전자가 단편적이었을 뿐만 아니라 개체에 적용하기 어려운 문제점이 있었다.
In general, research has been conducted on the correlation between radiation and cancer incidence, in particular, immunogenic response, but many disturbance variables have been impeded that hinder the reliability of the results. This is because most of the previous studies have used cancer cells or general mice, not only the expressed immunogenes were fragmentary but also difficult to apply to individuals.
종래 암 연구를 위하여 세포를 이용하는 방법은, 면역유전자를 변경하거나 암 발생에서 중요한 p53이 결여된 암 세포에 방사선을 조사하였기 때문에 정상 세포의 반응과는 근본적으로 달라 그 결과를 개체에 적용할 수 없는 문제점이 있었으며,Conventional methods of using cells for cancer research are fundamentally different from the response of normal cells because they irradiated cancer cells that altered the immunogene or lacked p53, which is important in cancer development. There was a problem,
일반 마우스를 이용하여 면역유전자 반응을 평가하였기 때문에 발현 면역유전자가 다양하였을 뿐만 아니라 암 발생이 특정 장기에 한정되지 않았기 때문에 면역유전자 반응을 해석하기 어려운 문제점이 있었다.Since the immune response was evaluated using a general mouse, the expression immunogenes were not only diverse, but there was a problem that it was difficult to interpret the immune response because cancer was not limited to specific organs.
상기와 같은 문제점을 감안한 본 발명이 해결하고자 하는 과제는, 교란 변수의 개입을 방지하여 조사된 방사선에 특이하게 반응하는 면역유전자를 명확하게 판단할 수 있는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법과, 그 검출 방법에 따라 검출된 흉선암 발병 조절 면역유전자군을 제공함에 있다.
In view of the above problems, the problem to be solved by the present invention is to prevent the involvement of disturbance variables and to clearly determine the immunogenes that respond specifically to the irradiated radiation cancer control modulated immunogenes in the mouse irradiated radiation To provide a method for detecting, and the thymic cancer onset control immunogene group detected according to the detection method.
상기와 같은 과제를 해결하기 위한 본 발명, 즉 전리 방사선 조사된 마우스에서 암 발병 조정 면역유전자를 검출하는 방법은, a) 특정 장기의 세포에 발암 면역유전자가 삽입된 AKR/J 마우스를 다수 준비하는 단계와, b) 상기 AKR/J 마우스를 세 개의 그룹으로 분할하고, 제1그룹의 AKR/J 마우스에 고선량률 전리 방사선을 조사 후 성장시키고, 제2그룹의 AKR/J 마우스에 저선량률 전리 방사선을 조사한 후 성장시키고, 나머지 제3그룹의 AKR/J 마우스는 일반 환경에서 성장시키는 단계와, c) 상기 b) 단계를 수행하면서 제1그룹 또는 제2그룹의 AKR/J 마우스 중 죽은 마우스의 흉선을 채취하여 방사선 조사전 장기의 중량에 비해 2배 이상 증가한 것을 암 발생된 것으로 진단하는 단계와, d) 상기 제3그룹의 AKR/J 마우스가 최초 죽는 시점에서 제1그룹, 제2그룹 및 제3그룹의 모든 AKR/J 마우스를 희생시켜 흉선을 추출하는 단계와, e) 상기 d) 단계에서 추출된 장기 중 방사선을 조사하지 않은 동일 연령의 AKR/J 마우스의 흉선과 중량 변화가 없는 흉선만을 선별하여 면역유전자 분석을 수행하여 증감한 면역유전자를 검출하는 단계와, f) 상기 검출된 면역유전자를 2배 이상 증가한 면역유전자와 2배 미만 증가 또는 감소한 면역유전자를 분류하여, 저선량률 조사시 특이하게 증가하여 면역반응을 발생시키는 유전자와, 고선량률 조사시 특이하게 감소하여 면역반응을 저하시키는 유전자를 분류하는 단계를 포함한다.In order to solve the above problems, the present invention, that is, a method for detecting cancer-mediated immunogenic genes in ionizing radiation-irradiated mice, a) preparing a large number of AKR / J mice in which a carcinogenic immunogene is inserted into cells of specific organs B) dividing the AKR / J mice into three groups, irradiating the high-dose ionizing radiation to the AKR / J mice of the first group, and growing the low-dose ionizing radiation to the AKR / J mice of the second group. And then grow the remaining AKR / J mice of the third group in a general environment, and c) the thymus of dead mice among the AKR / J mice of the first group or the second group while performing the step b). Diagnosing cancer as more than two times greater than the weight of the organ before irradiation, and d) the first, second and third groups of AKR / J mice of the third group. 3 groups Extracting thymus at the expense of all AKR / J mice; Performing a genetic analysis to detect the increased or decreased immunogenes, f) classifying the immunogenes in which the detected immunogenes are more than doubled and the immunogenes which are increased or decreased by less than 2 times, and are specifically increased during low dose irradiation. And classifying genes that generate an immune response and genes that are specifically reduced during high dose irradiation to reduce the immune response.
또한 전리 방사선 조사된 마우스에서 검출된 흉선암 발병 조절 면역유전자군은, 흉선 세포에 발암 면역유전자가 삽입된 마우스에 고선량률 또는 저선량률의 방사선을 조사하였을 때, 증가 또는 감소하는 흉선암 발병 조절 면역유전자로서, 저선량률의 방사선 조사시 증가하여 면역반응을 향상시키는 유전자로 Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 및 Lirb3인 것을 특징으로 한다.
In addition, the thymic cancer incidence-regulated immunogenes detected in ionizing-irradiated mice have increased or decreased thymus cancer incidence-regulated immunity when irradiated with high or low doses of radiation in mice in which thymic cells have carcinogenic immunogenic genes. As a gene, Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3, and Lirb3 are genes that increase when irradiated at a low dose rate and improve an immune response.
상기와 같이 구성되는 본 발명, 즉 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자 검출 방법은, 특정 장기의 세포에 발암 면역유전자가 삽입되어 암시작인자로 작용하는 AKR/J 마우스를 시험대상으로 고선량률과 저선량률의 방사선을 조사하고, 그 AKR/J 마우스가 죽기 시작하는 때에 암이 발생한 장기를 채취하여 암 발생단계를 고정하며, 채취된 장기의 무게가 방사선 조사되지 않은 장기의 무게와 동일한 것을 선별하고, 방사선 조사에 따른 면역유전자 반응을 해석함으로써, 교란 변수의 개입을 방지하여 방사선에 특이하게 반응하는 면역유전자를 정확하게 검출할 수 있는 효과가 있다.The present invention constituted as described above, that is, the method for detecting cancer onset immunogenic gene in ionizing irradiated mice, AKR / J mice that act as cancer initiation factors by inserting a carcinogenic immunogene into cells of specific organs, Investigate the dose rate and low dose rate radiation, collect organs with cancer when the AKR / J mouse begins to die, fix the stage of cancer development, and determine that the weight of the collected organs is the same as the weight of the unirradiated organs. By screening and analyzing the immune gene response according to irradiation, there is an effect that can accurately detect the immunogene that specifically reacts to radiation by preventing the intervention of disturbing variables.
또한 채취된 장기를 마우스 조직분석용 면역유전자 분석 시스템을 이용하여 분석함으로써, 타 종과의 유전적 중복성을 감소시켜, 특정 암 발생을 진단하고, 질병의 진행정도를 추시할 수 있게 되어, 진단키트 등의 응용분야에 적용하기가 용이한 효과가 있다.
In addition, by analyzing the collected organs using an immunogenic analysis system for mouse tissue analysis, it is possible to reduce the genetic redundancy with other species, diagnose specific cancer occurrences and follow the disease progression, diagnostic kit There is an effect that is easy to apply to applications such as.
도 1은 본 발명의 바람직한 실시예에 따른 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 순서도이다.
도 2는 방사선이 비조사된 그룹, 고선량률 방사선이 조사된 그룹, 저선량률 방사선이 조사된 그룹의 발생율을 비교한 그래프이다.
도 3은 저선량률의 방사선을 조사한 경우에 증가하는 면역유전자들이 면역반응에 기여함을 나타낸 관계도이다.
도 4는 고선량률의 방사선을 조사한 경우에 감소하는 면역유전자들이 면역반응을 저하시킴을 나타낸 관계도이다.1 is a flow chart for detecting cancer onset immunogenic genes in ionized irradiated mice according to a preferred embodiment of the present invention.
Figure 2 is a graph comparing the incidence rate of the group irradiated with radiation, the group irradiated with high dose rate radiation, the group irradiated with low dose rate radiation.
Figure 3 is a relationship showing that the increase in the immune response to the immune response when irradiated with a low dose rate of radiation.
Figure 4 is a relationship showing that the immunogenes that decrease when the radiation dose of high dose decreases the immune response.
이하, 상기와 같이 구성되는 본 발명, 즉 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법과 그 방법으로 검출된 흉선암 발병 조절 특이 면역유전자군에 대하여 첨부한 도면을 참조하여 상세히 설명한다.
Hereinafter, with reference to the accompanying drawings of the present invention, that is, a method for detecting cancer onset regulatory immunogenes in an ionizing radiation-exposed mouse and a thymic cancer onset regulation specific immunogene group detected by the method as described above will be described in detail. do.
도 1은 본 발명의 바람직한 실시예에 따른 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 순서도이다.1 is a flow chart for detecting cancer onset immunogenic genes in ionized irradiated mice according to a preferred embodiment of the present invention.
도 1을 참조하면 특정 장기의 세포에 발암 면역유전자가 삽입된 AKR/J 마우스를 다수 준비하는 단계(S11)와, 상기 AKR/J 마우스를 각각 고선량률 전리 방사선을 조사하는 제1그룹, 저선량률 전리 방사선을 조사하는 제2그룹, 전리 방사선을 조사하지 않는 제3그룹으로 분할하는 단계(S12)와, 상기 제1그룹의 AKR/J 마우스에 고선량률 전리 방사선을 조사하고, 상기 제2그룹의 AKR/J 마우스에 저선량률 전리 방사선을 조사하는 단계(S13)와, 상기 제1그룹 또는 제2그룹의 AKR/J 마우스 중 죽은 마우스의 특정 장기를 채취하여 방사선 조사전 장기의 중량에 비해 2배 이상 증가한 것을 암 발생된 것으로 진단하는 단계(S14)와, 제3그룹의 AKR/J 마우스가 최초 죽는 시점에서 제1그룹, 제2그룹 및 제3그룹의 모든 AKR/J 마우스를 희생시켜 해당 장기를 추출하는 단계(S15)와, 상기 추출된 장기 중 방사선을 조사하지 않은 동일 월령의 AKR/J 마우스의 장기와 중량 변화가 없는 장기만을 선별하여 면역유전자 분석을 수행하는 단계(S16)와, 상기 저선량률의 전리 방사선을 조사하였을 때 증가하여 면역반응을 향상시키는 유전자와, 상기 고선량률의 전리 방사선을 조사하였을 때 감소하여 면역반응을 저하시키는 유전자를 분류하는 단계(S17)를 포함한다.
Referring to Figure 1 preparing a plurality of AKR / J mice with a carcinogenic immunogene inserted into cells of a specific organ (S11), the first group to irradiate the high dose rate ionizing radiation to the AKR / J mice, respectively, low dose rate Dividing into a second group irradiated with ionizing radiation and a third group not irradiating with ionizing radiation (S12), and irradiating high-dose rate ionizing radiation to the AKR / J mice of the first group, Irradiating low-dose-rate ionizing radiation to AKR / J mice (S13), and collecting specific organs of dead mice in the first or second group of AKR / J mice, which are twice the weight of the organs before irradiation. Diagnosing the abnormal increase as cancer has occurred (S14), and at the time of the first death of the AKR / J mice of the third group, all AKR / J mice of the first group, the second group, and the third group are sacrificed to the corresponding organs. Extracting step (S15) and the weight Selecting only the organs of the same age AKR / J mice that were not irradiated and the organs without weight change among the selected organs to perform immunogenetic analysis (S16) and increased when the low-dose ionizing radiation was irradiated And a step of classifying the gene for enhancing the immune response and the gene for decreasing the immune response when irradiated with the high-dose ionizing radiation (S17).
이하, 상기와 같이 이루어지는 본 발명의 바람직한 실시예에 따른 전리 방사선 조사된 마우스에 암 발병 조절 면역유전자를 검출하는 방법을 보다 상세히 설명한다.
Hereinafter, a method of detecting cancer onset control immunogenes in an ionized radiation-treated mouse according to a preferred embodiment of the present invention will be described in more detail.
먼저, S11단계에서는 특정 장기의 세포에 발암 면역유전자가 삽입된 AKR/J 마우스를 다수 준비한다. 특히 실험을 위하여 일본 SLC사에서 구입한 6주령의 암컷 AKR/J 마우스를 이용하였으며, 흉선세포에 발암 면역유전자가 삽입되어 흉선암 시작인자로 작용하는 특성의 AKR/J 마우스를 사용하였다.
First, in step S11, a large number of AKR / J mice in which a carcinogenic immunogene is inserted into cells of a specific organ are prepared. In particular, 6-week-old female AKR / J mice purchased from SLC, Japan, were used for the experiment, and AKR / J mice having a characteristic of acting as a thymic cancer starter by inserting a carcinogenic immunogene into thymic cells were used.
이러한 흉선암 시작인자인 AKR/J 마우스를 S12단계와 같이 세 그룹으로 나누고, S13단계에서는 상기 제1그룹은 고선량률 전리 방사선을 조사하고, 제2그룹은 저선량률의 전리 방사선을 조사하였으며, 나머지 제3그룹은 방사선을 조사하지 않은 상태로 사육한다.
The AKR / J mouse, the thymic cancer starter, was divided into three groups as in step S12. In step S13, the first group was irradiated with high dose rate ionizing radiation, and the second group was irradiated with low dose rate ionizing radiation. The third group is raised without irradiation.
상기 제1그룹에 고선량률 전리 방사선을 조사하는 장치로는 감마선 발생장치(IBL 147C, CIS bio-international, France)를 사용하여 최종선량이 4.5Gy에 도달하도록 0.8Gy/분의 선량으로 감마선(Cs-137)을 조사한다.As a device for irradiating the high dose rate ionizing radiation to the first group, a gamma ray (Cs) at a dose of 0.8 Gy / min is used to achieve a final dose of 4.5 Gy using a gamma ray generator (IBL 147C, CIS bio-international, France). -137).
또한 상기 제2그룹은 0.7mGy/시간의 저선량률의 감마선(Cs-137)이 조사되는 환경에서 누적 선량이 4.5Gy에 이르도록 조사하며, 제3그룹의 AKR/J 마우스는 방사선이 조사되지 않는 일반 환경에서 사육한다.
In addition, the second group is irradiated so that the cumulative dose reaches 4.5Gy in the environment irradiated with a low dose rate gamma ray (Cs-137) of 0.7mGy / hour, the third group AKR / J mice are not irradiated Breed in general environment.
그 다음, S14단계에서는 상기 S13단계의 수행과정에서 제1 내지 제3그룹에 속한 AKR/J 마우스가 죽은 경우 그 죽은 마우스를 부검하여 흉선을 채취한다. Next, in step S14, when the AKR / J mice belonging to the first to third groups in the process of step S13 are dead, the dead mice are autopsied to collect thymus.
이때, 채취한 흉선의 무게가 방사선을 조사하지 않은 동일 월령의 다른 AKR/J 마우스의 평균 흉선 무게의 2배가 넘는 경우 흉선암이 발병한 것으로 판단한다.
In this case, when the weight of the collected thymus is more than twice the mean thymus weight of other AKR / J mice of the same age without irradiation, it is determined that the thymic cancer has occurred.
도 2는 각 시험 그룹에서 흉선암에 발병에 의해 죽은 마우스의 누적 수를 100분율로 표시한 그래프이다.FIG. 2 is a graph showing the cumulative number of mice killed by onset of thymic cancer in each test group at a fraction of 100. FIG.
도 2를 참조하면, 저선량률 방사선이 조사된 마우스 그룹이 고선량률 방사선에 이 조사된 마우스 그룹에 비교하여 흉선암의 발병률이 낮은 것을 알 수 있다.
Referring to FIG. 2, it can be seen that the group of mice irradiated with low dose radiation has a lower incidence of thymic cancer than the group of mice irradiated with high dose radiation.
그 다음, S15단계에서는 상기 제3그룹의 AKR/J 마우스가 최초 폐사하였을 때를 기준으로 모든 AKR/J 마우스를 희생시켜 각 AKR/J 마우스로부터 흉선을 채취한다. Next, in step S15, the thymus is collected from each AKR / J mouse at the expense of all AKR / J mice as the first time the third group of AKR / J mice dies.
일반 환경에서 사육되는 제3그룹의 AKR/J 마우스도 흉선세포에 발암 면역유전자가 삽입된 것으로 흉선암이 발생하게 되어 소정의 시간이 경과하면 폐사하게 된다. 실험적으로 150일 만에 최초 폐사가 발견되었다.AKR / J mice of the third group bred in a general environment also have carcinogenic immunogenic genes inserted into thymic cells, causing thymic cancer to die after a predetermined time. Experimentally, the first mortality was found in 150 days.
이처럼 흉선암이 발생되는 단계를 고정하여 교란 변수의 개입을 방지하였다.
Thus, the stage of thymic cancer was fixed to prevent the intervention of disturbance variables.
그 다음, S16단계에서는 상기 채취한 흉선 중 무게의 변화가 없는 흉선들 만을 액체 질소에 담근 후, 면역유전자 분석을 수행한다.Subsequently, in step S16, only the thymus which have no change in weight among the collected thymus are immersed in liquid nitrogen, and then immunogen analysis is performed.
이때의 면역유전자 분석의 방법으로는 채취된 AKR/J 마우스의 흉선세포를 분쇄하여 Agilent 사의 마이크로 어레이키트를 이용하여 검출한 결과로서, 두 배 이상 증가 발현하는 면역유전자를 검출한다.
In this method of immunogene analysis, the thymus cells of the collected AKR / J mice are pulverized and detected using Agilent's microarray kit.
그 다음, S17단계에서는 저선량률과 고선량률 각각의 방사선 조사에서 특이하게 증가 또는 감소되는 유전자에 의한 면역반응의 변화를 분석한다.
Next, in step S17, changes in the immune response caused by the genes that are specifically increased or decreased in the irradiation of the low dose rate and the high dose rate, respectively.
이러한 분석으로 검출된 두 배 이상 증가 발현한 유전자는 아래의 표 1과 같다.Genes expressed more than twice as much as detected by this analysis are shown in Table 1 below.
또한, 상기 마이크로 어레이법으로 분석한 결과, 두 배 미만으로 증가 발현된 면역유전자는 아래의 표 2와 같다.In addition, as a result of analysis by the microarray method, the immunogene expressed by less than twice as shown in Table 2 below.
상기 표 1과 표 2에는 상기 마이크로 어레이 실험 후 칩을 스캔할 때, 고선량률 조사와 저선량률 조사에서 각 유전자가 비조사군과 비교하여 얼마만큼 발현하고 있는지를 나타내는 절대치이다.Table 1 and Table 2 are absolute values indicating how much each gene is expressed in the high dose rate irradiation and the low dose rate irradiation when the chip is scanned after the microarray experiment.
즉, 1은 비조사군과 동일하고, 2는 두 배의 발현을 나타냄을 뜻한다.
That is, 1 means the same as the non-irradiated group, 2 means that the expression is double.
이와 같이 흉선암 발병 조절 특이 면역유전자는 고선량률과 저선량률 방사선 조사 후, 흉선에서 특이하게 증감하는 면역유전자군이며, 이러한 면역유전자군의 프로파일을 이용하여 다양한 선량 및 선량률에 반응하면서 흉선암의 발생단계를 진단할 수 있다.As described above, specific immune genes that control the development of thymic cancer are immunogenic groups that specifically increase or decrease in the thymus after irradiation with high dose rate and low dose rate. Diagnose the steps.
특히 흉선암의 발생 특성을 고려하여 암 발생진행단계를 DNA의 회복, DNA의 손상신호, 세포주기, 암 진행도 지표, p53 신호계, 세포고사, T-와 B-세포활성의 7단계로 구분하여 면역유전자의 증감을 구분하여 면역유전자 프로파일을 구성할 수 있다.
In particular, the cancer developmental stage is divided into seven stages of DNA recovery, DNA damage signal, cell cycle, cancer progression indicator, p53 signaling system, apoptosis, and T- and B-cell activity. Differentiation of immunogenes can be used to construct immunogenic profiles.
이러한 면역유전자 프로파일은 응용분야로서 흉선암 진단키트를 제작하는데 사용이 가능하며, 암환자의 암 진행 및 치료정도를 평가할 수 있으며, 산업 및 의료 종사자의 방사선 피폭과 발암과의 상관성을 평가할 수 있는 지표로 사용할 수 있다.These immunogene profiles can be used to manufacture thymic cancer diagnostic kits, to evaluate cancer progression and treatment of cancer patients, and to evaluate the correlation between radiation exposure and carcinogenesis of industrial and medical workers. Can be used as
또한 방사선과 암 발생의 인과관계를 평가하거나, 방사선 피폭에 대한 생물학적 선량평가를 위한 새로운 지표 면역유전자로 활용이 가능하며, 저선량률 방사선에 의한 흉선암 억제효과를 평가하는 지표 면역유전자로 활용이 가능하게 된다.
In addition, it can be used as a new indicator immunogene for evaluating the causal relationship between radiation and cancer occurrence or as a biological dose assessment for radiation exposure, and as an indicator immunogene for evaluating thymic cancer suppression effect by low dose rate radiation. do.
도 3은 저선량률의 방사선을 조사한 경우에 증가하는 면역유전자들이 면역반응에 기여함을 나타낸 관계도이다.Figure 3 is a relationship showing that the increase in the immune response to the immune response when irradiated with a low dose rate of radiation.
도 3을 참조하면, 저선량률의 방사선을 조사한 경우 Cd51, Fcgr3, Pycard 유전자가 증가되면서 세포의 사멸을 유도함과 동시에 Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 및 Lirb3 유전자를 자극하여, T, B, NK 세포의 분화(Jag2), B세포(Igh6, MGC60843) 및 APC 세포의 활성화(Fcgr2b, Fcgr3), 항암면역의 작용(Lirb3)을 촉진시켜 흉선암의 발병을 낮출 수 있으며, 수명을 연장시키는 것을 알 수 있다.
Referring to Figure 3, when the radiation dose of low dose rate Cd51, Fcgr3, Pycard genes are increased to induce cell death and at the same time stimulate the Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 and Lirb3 genes, T, B, NK Promote differentiation of cells (Jag2), B cells (Igh6, MGC60843) and activation of APC cells (Fcgr2b, Fcgr3), anticancer immunity (Lirb3), which can lower the onset of thymic cancer and prolong life Can be.
또한 도 4는 고선량률의 방사선을 조사한 경우에 감소하는 면역유전자들이 면역반응을 저하시킴을 나타낸 관계도이다.In addition, Figure 4 is a relationship showing that the reduced immunogenes in the immune response when irradiated with a high dose rate of radiation.
도 4를 참조하면, 세포사멸(Sp3), T 세포, NK세포가 생존하고(Il15,Cd3e), 임파세포발달(Rag2, Cd28, Cbfb), T 세포, NK 세포가 활성화(Traf6, Il2ra)에 관여하는 유전자의 발현을 억제하여 암발생을 촉진시킨다. 또한 암 발생을 억제하려는 움직임도 일어나 T 세포 발달을 촉진시키는 Ifag, Igbp1, Il7 유전자와 흉선세포 자체에서 Cxcr4와 Pik3el이 발현되었으나 억제력은 상대적으로 낮게 검출되었다.
Referring to Figure 4, apoptosis (Sp3), T cells, NK cells survive (Il15, Cd3e), lymphocyte development (Rag2, Cd28, Cbfb), T cells, NK cells are activated (Traf6, Il2ra) Promotes cancer by inhibiting the expression of genes involved. In addition, Cxcr4 and Pik3el were expressed in Ifag, Igbp1 and Il7 genes and thymic cells themselves, which promote T cell development.
전술한 바와 같이 본 발명에 따른 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자 검출하는 방법 및 면역유전자군에 대하여 바람직한 실시예를 들어 상세히 설명하였지만, 본 발명은 전술한 실시예들에 한정되는 것이 아니고, 특허청구범위와 발명의 상세한 설명 및 첨부한 도면의 범위 안에서 여러 가지로 변형하여 실시하는 것이 가능하고 이 또한 본 발명에 속한다.
As described above, a method and an immunogene group for detecting cancer onset control genes in ionizing irradiated mice according to the present invention have been described in detail with reference to preferred embodiments, but the present invention is not limited to the above embodiments. It is possible to carry out various modifications within the scope of the claims and the detailed description of the invention and the accompanying drawings, which also belong to the invention.
Claims (7)
b) 상기 AKR/J 마우스를 세 개의 그룹으로 분할하고, 제1그룹의 AKR/J 마우스에 고선량률 전리 방사선을 조사 후 사육하고, 제2그룹의 AKR/J 마우스에 저선량률 전리 방사선을 조사한 후 사육하고, 나머지 제3그룹의 AKR/J 마우스는 일반 환경에서 사육하는 단계;
c) 상기 b) 단계를 수행하면서 제1그룹 또는 제2그룹의 AKR/J 마우스 중 죽은 마우스의 흉선을 채취하여 방사선 조사전 장기의 중량에 비해 증가한 것을 암 발생된 것으로 진단하는 단계;
d) 상기 제3그룹의 AKR/J 마우스가 최초 죽는 시점에서 제1그룹, 제2그룹 및 제3그룹의 모든 AKR/J 마우스를 희생시켜 흉선을 추출하는 단계;
e) 상기 d) 단계에서 추출된 장기 중 방사선을 조사하지 않은 동일 연령의 AKR/J 마우스의 장기와 비교하여 중량 변화가 없는 흉선세포만을 선별하여 면역유전자 분석을 수행하여 증감한 면역유전자를 검출하는 단계;
f) 상기 검출된 면역유전자를 2배 이상 증가한 면역유전자와 2배 미만 증가 또는 감소한 면역유전자를 분류하여, 저선량률 조사시 특이하게 증가하여 면역반응을 발생시키는 유전자와, 고선량률 조사시 특이하게 감소하여 면역반응을 저하시키는 유전자를 분류하는 단계를 포함하는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법.
a) preparing a plurality of AKR / J mice having a carcinogenic immunogene inserted into cells of a specific organ;
b) The AKR / J mice were divided into three groups, the AKR / J mice of the first group were raised after irradiation with high dose rate ionizing radiation, and the AKR / J mice of the second group were exposed to low dose rate ionizing radiation. Breeding, and rest of the third group of AKR / J mice in a general environment;
c) extracting the thymus of dead mice of the AKR / J mice of the first group or the second group while performing the step b) and diagnosing cancer increase as compared to the weight of the organ before irradiation;
d) extracting the thymus at the expense of all AKR / J mice of the first, second and third groups at the time of the first death of the third group of AKR / J mice;
e) detecting sensitized immunogenes by performing immunogenetic analysis by selecting only thymic cells without weight change in comparison with the organs of the same age AKR / J mice not irradiated among the organs extracted in step d) step;
f) classifying the detected immunogenes by more than two times the immunogenes and by less than two times the increase or decrease of the immunogenes, the genes that specifically increase during the low dose rate irradiation to generate an immune response, and specifically decreases during the high dose rate irradiation And classifying genes that lower the immune response.
상기 b) 단계는,
상기 제1그룹에 최종선량이 4.5Gy에 도달하도록 0.8Gy/분의 선량으로 감마선(Cs-137)을 조사하며,
상기 제2그룹은 0.7mGy/시간의 저선량률의 감마선(Cs-137)이 조사되도록 하여 누적 선량이 4.5Gy에 이를 때까지 조사하는 것을 특징으로 하는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법.
The method of claim 1,
The step b)
Gamma rays (Cs-137) are irradiated to the first group at a dose of 0.8 Gy / min to reach a final dose of 4.5 Gy,
In the second group, a gamma ray having a low dose rate of 0.7 mGy / hour (Cs-137) is irradiated until the cumulative dose reaches 4.5 Gy. How to detect.
상기 e) 단계에서 검출된 면역유전자군의 증감 프로파일은,
흉선암 진단키트 제작, 암환자의 암 진행 및 치료정도를 평가, 산업 및 의료 종사자의 방사선 피폭과 발암과의 상관성을 평가, 방사선과 암 발생의 인과관계를 평가, 방사선 피폭에 대한 생물학적 선량평가 또는 저선량률 방사선에 의한 흉선암 억제효과 평가의 지표로 사용되는 것을 특징으로 하는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법.
The method according to claim 1 or 2,
The increase and decrease profile of the immunogene group detected in step e),
Manufacture of thymic cancer diagnostic kits, evaluation of cancer progression and treatment of cancer patients, evaluation of the correlation between radiation exposure and carcinogenesis of industrial and medical workers, evaluation of the causal relationship between radiation and cancer occurrence, biological dose assessment of radiation exposure or low A method for detecting cancer-controlled immunogenes in ionized irradiated mice, characterized in that it is used as an index for evaluating the effect of inhibiting thymic cancer by dose rate radiation.
상기 f) 단계에서, 저선량률의 방사선 조사시 증가하여, 면역반응을 증가시키는 유전자는, Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 및 Lirb3인 것을 특징으로 하는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법.
The method according to claim 1 or 2,
In step f), the genes that increase upon irradiation at low dose rate and increase the immune response are Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 and Lirb3, characterized in that A method for detecting cancer onset control genes.
상기 f) 단계에서, 고선량률의 방사선 조사시 감소하여, 면역반응을 저하시키는 유전자는, Sp3, Il15, Cd3e, Rag2, Cd28, Cbfb, Traf6 및 Il2ra인 것을 특징으로 하는 전리 방사선 조사된 마우스에서 암 발병 조절 면역유전자를 검출하는 방법.
The method according to claim 1 or 2,
In the step f), the genes that decrease when irradiated with high dose rate and lower the immune response are Sp3, Il15, Cd3e, Rag2, Cd28, Cbfb, Traf6 and Il2ra, the cancer in the ionizing irradiated mouse, characterized in that A method for detecting onset regulatory immunogenes.
저선량률의 방사선 조사시 증가하여 면역반응을 향상시키는 유전자로 Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3 및 Lirb3인 것을 특징으로 하는 전리 방사선 조사된 마우스에서 검출된 흉선암 발병 조정 면역유전자군.
As a thymic cancer onset-controlling immunogene that increases or decreases when high dose rate or low dose rate radiation is irradiated to a mouse in which a thymic cell has a carcinogenic immunogene inserted therein,
Genes that enhance immune response by increasing dose at low dose rate are Cd51, Fcgr3, Pycard, Jag2, Igh6, MGC60843, Fcgr2b, Fcgr3, and Lirb3. Genetic group.
상기 고선량률의 방사선 조사시 감소하여, 면역반응을 저하시키는 유전자는, Sp3, Il15, Cd3e, Rag2, Cd28, Cbfb, Traf6 및 Il2ra인 것을 특징으로 하는 전리 방사선 조사된 마우스에서 검출된 흉선암 발병 조정 면역유전자군.
The method of claim 6,
Genes that decrease when irradiating at high dose rates and lower the immune response are Sp3, Il15, Cd3e, Rag2, Cd28, Cbfb, Traf6, and Il2ra. Immunogene group.
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| CN103749388A (en) * | 2014-01-16 | 2014-04-30 | 中国科学技术大学 | Method for breeding IL-12p40 (-/-) IL-2R alpha (-/-) mice used as hepatic fibrosis and primary biliary cirrhosis animal models |
| WO2018004062A1 (en) * | 2016-06-29 | 2018-01-04 | 한국수력원자력 주식회사 | Apoptosis regulatory gene detected in irradiated-thymic lymphoma cell and method for detecting same |
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| CN103749388A (en) * | 2014-01-16 | 2014-04-30 | 中国科学技术大学 | Method for breeding IL-12p40 (-/-) IL-2R alpha (-/-) mice used as hepatic fibrosis and primary biliary cirrhosis animal models |
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| WO2018004062A1 (en) * | 2016-06-29 | 2018-01-04 | 한국수력원자력 주식회사 | Apoptosis regulatory gene detected in irradiated-thymic lymphoma cell and method for detecting same |
| JP2019523655A (en) * | 2016-06-29 | 2019-08-29 | コリア ハイドロ アンド ニュークリアー パワー カンパニー リミテッド | Cell death control gene excavated from irradiated thymic lymphoma cells and detection method thereof |
| US11230740B2 (en) | 2016-06-29 | 2022-01-25 | Korea Hydro & Nuclear Power Co., Ltd. | Apoptosis regulatory gene detected in irradiated-thymic lymphoma cell and method for detecting same |
| WO2019066124A1 (en) * | 2017-09-26 | 2019-04-04 | 한국수력원자력 주식회사 | Telomere-controlling gene family discovered in mouse thymus lymphoma cell irradiated with low-dose rate low-level radiation, and method for detecting same |
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