KR20220011831A - Use of EMP2 for the diagnosis of viral pneumonia or sepsis - Google Patents
Use of EMP2 for the diagnosis of viral pneumonia or sepsis Download PDFInfo
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- KR20220011831A KR20220011831A KR1020200090156A KR20200090156A KR20220011831A KR 20220011831 A KR20220011831 A KR 20220011831A KR 1020200090156 A KR1020200090156 A KR 1020200090156A KR 20200090156 A KR20200090156 A KR 20200090156A KR 20220011831 A KR20220011831 A KR 20220011831A
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Abstract
Description
본 발명은 EMP2의 바이러스성 폐렴 또는 패혈증의 진단을 위한 용도에 관한 것이다.The present invention relates to the use of EMP2 for the diagnosis of viral pneumonia or sepsis.
최근 중국 우한에서 발생하여 전 세계적으로 유행하고 있는 2019 신종코로나바이러스와 같은 다양한 호흡기 바이러스로 인하여 감염자 및 사망자가 증가하는 것으로 보고되고 있다.It is reported that the number of infections and deaths is increasing due to various respiratory viruses such as the 2019 novel coronavirus, which recently occurred in Wuhan, China and is spreading around the world.
2019 신종코로나바이러스는 다양한 코로나 바이러스 중 하나로, 코로나 바이러스는 단일가닥 양성 RNA를 게놈으로 가지고, 외피가 있는 바이러스로 1937년 처음 발견된 이후 사람을 포함하여 다양한 동물에게서 분리되었다. 코로나 바이러스는 4개의 그룹으로 나눌 수 있는데, 이중 α-코로나 코로나바이러스 및 β-코로나 바이러스는 주로 포유류에 감염되고, γ-코로나 바이러스 및 δ-코로나 바이러스는 조류에 감염된다.The 2019 novel coronavirus is one of various coronaviruses. The coronavirus has a single-stranded positive RNA as its genome and is an enveloped virus that has been isolated from a variety of animals, including humans, since it was first discovered in 1937. Coronaviruses can be divided into four groups, of which α-coronavirus and β-coronavirus mainly infect mammals, and γ-coronavirus and δ-coronavirus infect birds.
코로나 바이러스의 감염은 다양한 연구가 진행되고 있으나, 주로 폐세포에 존재하는 바이러스 수용체의 발현이 바이러스가 폐세포로 침입하여 폐렴 또는 패혈증과 같은 질환을 발병시키는 요인으로 주목되고 있다.Although various studies on corona virus infection are being conducted, mainly the expression of virus receptors present in lung cells is attracting attention as a factor causing the virus to invade lung cells and cause diseases such as pneumonia or sepsis.
코로나 바이러스에 의해 일부 사람은 감염이 잘 되지만 많은 사람들은 무증상으로 감염이 잘 되지 않거나 증상이 약하게 나타나고 있으며, 이러한 증상의 차이 또한 바이러스 침입에 영향을 주는 수용체 발현의 차이가 나타나기 때문으로 연구되어 지고 있다.Some people are infected well by the coronavirus, but many people are asymptomatic, and the infection is not well or the symptoms are weak. .
종래의 항바이러스 치료제는 바이러스를 공격하는 것으로 변이를 잘하는 바이러스에 의해 치료제가 무력화되는 단점이 존재한다. 이러한 문제로 바이러스에 의한 감염을 극복하기 위해서는 바이러스의 숙주인 인간이 바이러스에 대해 저항할 수 있는 새로운 방법이 필요한 상황이다. 특히 호흡기의 폐포에 감염을 일으키는 바이러스에 대해서는 폐포에서의 바이러스의 침투를 막는 것이 중요하다.Conventional antiviral therapeutic agents attack viruses, and there is a disadvantage in that the therapeutic agents are ineffective by viruses that mutate well. In order to overcome the infection caused by the virus due to this problem, a new method is required for humans, the host of the virus, to resist the virus. In particular, for viruses that infect the alveoli of the respiratory tract, it is important to prevent the virus from entering the alveoli.
이와 같은 상황에서 본 발명자들은 폐세포에 존재하는 EMP2의 발현 변화가 코로나 바이러스 감염 위험성에 미치는 영향을 연구함으로써, 본 발명을 완성하였다.In this situation, the present inventors completed the present invention by studying the effect of changes in the expression of EMP2 present in lung cells on the risk of corona virus infection.
본 발명은 EMP2의 바이러스성 폐렴 또는 패혈증의 진단을 위한 용도에 관한 것으로, EMP2의 발현 감소가 2019 신종코로나바이러스의 감염과 관련되어 있음을 확인하고, EMP2 단백질 또는 이를 암호화하는 유전자를 바이러스성 폐렴 또는 패혈증의 진단용 마커로 제공하고, EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 증가시키는 제제를 2019 신종코로나바이러스의 감염에 의한 폐렴 또는 패혈증의 치료제로 제공하는 것이다.The present invention relates to the use of EMP2 for the diagnosis of viral pneumonia or sepsis, confirming that the decrease in the expression of EMP2 is related to infection of the 2019 novel coronavirus, and converting the EMP2 protein or the gene encoding it to viral pneumonia or To provide as a diagnostic marker for sepsis, and to provide an agent that increases the expression level of EMP2 protein or a gene encoding it as a treatment for pneumonia or sepsis caused by infection with the 2019 novel coronavirus.
본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자를 포함하는 바이러스성 폐렴 또는 패혈증의 진단용 바이오마커를 제공한다.The present invention provides a biomarker for diagnosis of viral pneumonia or sepsis comprising the EMP2 protein or a gene encoding the same.
또한, 본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 진단하는 제제를 유효성분으로 포함하는 포함하는 바이러스성 폐렴 또는 패혈증의 진단용 조성물을 제공한다.In addition, the present invention provides a composition for diagnosis of viral pneumonia or sepsis comprising an agent for diagnosing the expression level of EMP2 protein or a gene encoding the same as an active ingredient.
또한, 본 발명은 환자의 조직에서 분리된 생물학적 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 측정하는 단계; 및 상기 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준이 정상 대조군에 비해 낮으면 바이러스성 폐렴이 발병할 가능성이 있는 것으로 판단하는 바이러스성 폐렴 또는 패혈증의 진단을 위한 정보 제공 방법을 제공한다.In addition, the present invention comprises the steps of measuring the expression level of the EMP2 protein or a gene encoding the same in a biological sample isolated from a patient's tissue; And when the expression level of the EMP2 protein or a gene encoding the same in the sample is lower than that of a normal control group, it provides an information providing method for diagnosing viral pneumonia or sepsis, which is determined to be likely to cause viral pneumonia.
또한, 본 발명은 대상체의 조직에서 분리된 생물학적 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 측정하는 단계; 및 시험물질을 처리한 후 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준이 시험물질을 처리하지 않은 질환 대상체에 비해 증가하면 바이러스성 폐렴 또는 패혈증의 예방 또는 치료용 제제로 판단하는 단계;를 포함하는 바이러스성 폐렴 또는 패혈증에 대한 예방 또는 치료용 제제의 스크리닝 방법을 제공한다.In addition, the present invention comprises the steps of measuring the expression level of the EMP2 protein or a gene encoding the same in a biological sample isolated from a tissue of a subject; And when the expression level of the EMP2 protein or the gene encoding the test substance increases compared to the disease subject not treated with the test substance after treatment with the test substance, judging as a preventive or therapeutic agent for viral pneumonia or sepsis; Viruses containing Provided is a screening method for a prophylactic or therapeutic agent for sexually transmitted pneumonia or sepsis.
또한, 본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 증가시키는 제제를 유효성분으로 포함하는 바이러스성 폐렴 또는 패혈증의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating viral pneumonia or sepsis, comprising an agent that increases the expression level of the EMP2 protein or a gene encoding the same as an active ingredient.
본 발명에 따르면, EMP2의 발현 감소가 2019 신종코로나바이러스의 감염과 관련되어 있음을 확인하고, EMP2 단백질 또는 이를 암호화하는 유전자를 바이러스성 폐렴 또는 패혈증의 진단용 마커로 제공하고, EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 증가시키는 제제를 2019 신종코로나바이러스의 감염에 의한 폐렴 또는 패혈증의 치료제로 제공될 수 있다.According to the present invention, it is confirmed that the decrease in the expression of EMP2 is related to the infection of the 2019 novel coronavirus, and the EMP2 protein or a gene encoding it is provided as a diagnostic marker for viral pneumonia or sepsis, and the EMP2 protein or a gene encoding the same An agent that increases the expression level of a gene may be provided as a treatment for pneumonia or sepsis caused by infection with the 2019 novel coronavirus.
도 1은 EMP2 결여 조건에서 바이러스의 침투와 관련된 유전자들의 발현 변화를 평가한 그래프이다.
도 2는 EMP2 결여 조건에서 2019 신종코로나바이러스의 수용체인 ACE2 및 DPP4의 발현 변화를 평가한 그래프이다.
도 3은 EMP2 결여 조건에서 2019 신종코로나바이러스의 수용체인 DPP4의 발현 변화를 western blot으로 분석한 사진이다.
도 4은 폐암 세포주에 담배 연기 농축액(cigarette smoke condensates, CSC) 또는 담배 연기 추출물(cigarette smoke extract, CSE) 처리에 따른 EMP2의 발현 변화를 평가한 사진이다.
도 5는 폐암 세포주에 니코틴 처리에 따른 EMP2의 발현 변화를 평가한 사진이다.
도 6는 EMP2 발현 억제에 따른 NF-kB의 활성화 변화를 평가한 사진이다.
도 7은 EMP2 발현 억제에 따른 사이토카인(cytokine) 유전자들의 발현 변화를 평가한 그래프다.
도 8은 EMP2 발현 억제에 따른 GPCR(G protein coupled receptor) 관련 유전자들의 발현 변화를 평가한 그래프이다.
도 9은 다이오스제닌 처리에 따른 EMP2의 발현 변화를 평가한 그래프이다.
도 10은 프로제스테론 처리에 따른 EMP2의 발현 변화를 평가한 그래프이다.
도 11은 레졸빈 처리에 따른 EMP2의 발현 변화를 평가한 그래프이다.1 is a graph evaluating the expression change of genes related to the penetration of the virus in the absence of EMP2 conditions.
2 is a graph evaluating the expression changes of ACE2 and DPP4, the receptors of the 2019 novel coronavirus, in the EMP2 absence condition.
3 is a photograph analyzed by western blot of the expression change of DPP4, a receptor of the 2019 novel coronavirus, under the condition of lack of EMP2.
Figure 4 is a photograph evaluating the expression change of EMP2 according to the treatment of cigarette smoke concentrate (cigarette smoke condensates, CSC) or cigarette smoke extract (CSE) in lung cancer cell lines.
5 is a photograph evaluating the expression change of EMP2 according to nicotine treatment in lung cancer cell lines.
6 is a photograph evaluating the activation change of NF-kB according to the suppression of EMP2 expression.
7 is a graph evaluating the expression change of cytokine genes according to the suppression of EMP2 expression.
8 is a graph evaluating the expression change of GPCR (G protein coupled receptor) related genes according to the suppression of EMP2 expression.
9 is a graph evaluating the expression change of EMP2 according to diosgenin treatment.
10 is a graph evaluating the expression change of EMP2 according to progesterone treatment.
11 is a graph evaluating the expression change of EMP2 according to the resolvin treatment.
본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.The terms used in this specification have been selected as currently widely used general terms as possible while considering the functions in the present invention, but these may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, and the like. In addition, in a specific case, there is a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the corresponding invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than the name of a simple term.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless defined otherwise, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.Numerical ranges are inclusive of the values defined in that range. Every maximum numerical limitation given throughout this specification includes all lower numerical limitations as if the lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes all higher numerical limitations as if the higher numerical limitation were expressly written. Any numerical limitation given throughout this specification shall include all numerical ranges within the broader numerical range, as if the narrower numerical limitation were expressly written down.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자를 포함하는 바이러스성 폐렴 또는 패혈증의 진단용 바이오마커를 제공한다.The present invention provides a biomarker for diagnosis of viral pneumonia or sepsis comprising the EMP2 protein or a gene encoding the same.
상기 바이러스는 2019 신종코로나바이러스이다. 신종 코로나 바이러스 뿐만 아니라 폐 포에 감염을 일으키는 바이러스를 모두 포함할 수 있다.The virus is the 2019 novel coronavirus. It can include not only the novel coronavirus, but also viruses that infect the alveoli.
또한, 본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 진단하는 제제를 유효성분으로 포함하는 포함하는 바이러스성 폐렴 또는 패혈증의 진단용 조성물을 제공한다.In addition, the present invention provides a composition for diagnosis of viral pneumonia or sepsis comprising an agent for diagnosing the expression level of EMP2 protein or a gene encoding the same as an active ingredient.
또한, 본 발명은 환자의 조직에서 분리된 생물학적 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 측정하는 단계; 및 상기 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준이 정상 대조군에 비해 낮으면 바이러스성 폐렴이 발병할 가능성이 있는 것으로 판단하는 바이러스성 폐렴 또는 패혈증의 진단을 위한 정보 제공 방법을 제공한다.In addition, the present invention comprises the steps of measuring the expression level of the EMP2 protein or a gene encoding the same in a biological sample isolated from a patient's tissue; And when the expression level of the EMP2 protein or a gene encoding the same in the sample is lower than that of a normal control group, it provides an information providing method for diagnosing viral pneumonia or sepsis, which is determined to be likely to cause viral pneumonia.
또한, 본 발명은 대상체의 조직에서 분리된 생물학적 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 측정하는 단계; 및 시험물질을 처리한 후 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준이 시험물질을 처리하지 않은 질환 대상체에 비해 증가하면 바이러스성 폐렴 또는 패혈증의 예방 또는 치료용 제제로 판단하는 단계;를 포함하는 바이러스성 폐렴 또는 패혈증에 대한 예방 또는 치료용 제제의 스크리닝 방법을 제공한다.In addition, the present invention comprises the steps of measuring the expression level of the EMP2 protein or a gene encoding the same in a biological sample isolated from a tissue of a subject; And when the expression level of the EMP2 protein or the gene encoding the test substance increases compared to the disease subject not treated with the test substance after treatment with the test substance, judging as a preventive or therapeutic agent for viral pneumonia or sepsis; Viruses containing Provided is a screening method for a prophylactic or therapeutic agent for sexually transmitted pneumonia or sepsis.
또한, 본 발명은 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 증가시키는 제제를 유효성분으로 포함하는 바이러스성 폐렴 또는 패혈증의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating viral pneumonia or sepsis, comprising an agent that increases the expression level of the EMP2 protein or a gene encoding the same as an active ingredient.
상기 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준을 증가시키는 제제는 사이코사포닌 D(saikosaponin D), 다이오스제닌 (diosgenin), 프로게스테론 (progesterone), 레졸빈(resolvin), 또는 레티노익산(retinoic acid)일 수 있으나, 이에 제한되는 것은 아니다.The agent for increasing the expression level of the EMP2 protein or a gene encoding it is psychosaponin D (saikosaponin D), diosgenin, progesterone, resolvin (resolvin), or retinoic acid (retinoic acid) However, the present invention is not limited thereto.
상기 약학적 조성물은 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 및 카타플라스마제로 이루어진 군으로부터 선택되는 하나 이상의 외용제 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in the form of one or more external preparations selected from the group consisting of creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastas, and cataplasmas.
본 발명의 약학적 조성물은 제형화를 위해 추가로 있는 약학적으로 허용가능한 담체 및 희석제를 포함할 수 있다. 상기 약학적으로 허용가능한 담체 및 희석제는 전분, 당, 및 만니톨과 같은 부형제, 칼슘 포스페이트 등과 같은 충전제 및 증량제, 카르복시메틸셀룰로오스, 히드록시프로필셀룰로오스 등과 같은 셀룰로오스 유도체, 젤라틴, 알긴산염, 및 폴리비닐 피롤리돈 등과 같은 결합제, 활석, 스테아린산 칼슘, 수소화 피마자유 및 폴리에틸렌 글리콜과 같은 윤활제, 포비돈, 크로스포비돈과 같은 붕해제, 폴리소르베이트, 세틸알코올, 및 글리세롤 등과 같은 계면활성제를 포함하나, 이에 한정되지 않는다. 상기 약학적으로 허용가능한 담체 및 희석제는 대상체에게 생물학적 및 생리학적으로 친화적인 것일 수 있다. 희석제의 예로는 염수, 수용성 완충액, 용매 및/또는 분산제(dispersion media)를 들 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier and diluent for formulation. The pharmaceutically acceptable carriers and diluents include starch, sugar, and excipients such as mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, alginate, and polyvinyl blood binders such as rolidone, lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone and crospovidone, surfactants such as polysorbates, cetyl alcohol, and glycerol does not The pharmaceutically acceptable carrier and diluent may be biologically and physiologically compatible with the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents, and/or dispersion media.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 바람직하게는 경구 투여된다. 또한 본 발명의 약학적 조성물의 투여량은 대상체의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and is preferably administered orally. In addition, the dosage of the pharmaceutical composition of the present invention varies depending on the subject's body weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of disease, but is not limited thereto.
이하, 본 발명의 이해를 돕기 위하여 실험예 및 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실험예 및 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실험예 및 실시예에 한정되는 것은 아니다. 본 발명의 실험예 및 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, experimental examples and examples will be described in detail to help the understanding of the present invention. However, the following experimental examples and examples are only to illustrate the content of the present invention, the scope of the present invention is not limited to the following experimental examples and examples. Experimental examples and examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
<실험예> 실험 재료 및 방법<Experimental example> Experimental material and method
하기의 실험예들은 본 발명에 따른 각각의 실시예에 공통적으로 적용되는 실험예를 제공하기 위한 것이다.The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.
1. 세포 및 배양 조건1. Cells and Culture Conditions
본 발명에서 사용된 EMP2-/- 마우스는 국립암센터의 이호박사와 공동으로 확립한 마우스로 EMP2-/- 마우스로부터 E13.5 단계의 embryo로부터 MEF(mouse embryonic fibroblast) 세포를 분리하고, DMEM 배지에서 37oC, 3% O2, 5% CO2 조건으로 배양하였다.The EMP2 -/- mouse used in the present invention was established jointly with Dr. Ho Lee of the National Cancer Center. MEF (mouse embryonic fibroblast) cells were isolated from the E13.5 stage embryo from the EMP2 -/- mouse, and DMEM medium was used. 37 o C, 3% O 2 , 5% CO 2 Incubated under conditions.
폐암 세포주인 A549 및 H1299 세포는 ATCC에서 구입하였고, RPMI 배지에서 37oC, 5% CO2 조건으로 배양되었다.Lung cancer cell lines A549 and H1299 cells were purchased from ATCC, and cultured in RPMI medium at 37 o C, 5% CO 2 conditions.
2. RNA seq 분석2. RNA seq analysis
본 발명에서는 특정 유전자의 발현 수준을 평가하기 위해서 RNA seq 방법을 이용하였다. 구체적으로 배양된 EMP2-/- MEF세포로부터 RNA를 trizol등을 이용하여 추출하고 이바이오젠에 RNA를 보내 RNA seq을 수행하였다.In the present invention, the RNA seq method was used to evaluate the expression level of a specific gene. Specifically, RNA was extracted from cultured EMP2 -/- MEF cells using trizol, etc., and RNA was sent to eBiogen to perform RNA seq.
3. 담배 추출물3. Tobacco Extract
본 발명에서 사용된 담배 연기 추출물 (cigarette smoke extract), 담배 연기 농축액 (cigarette smoke condensates)은 담배사업단의 동국대학교의 이무열 교수로부터 제공받았다.Tobacco smoke extract used in the present invention (cigarette smoke extract), cigarette smoke concentrate (cigarette smoke condensates) was provided by Professor Lee Mu-yeol of Dongguk University of the Tobacco Business Team.
니코틴 및 NKK (nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone)는 시그마에서 구입하였다.Nicotine and NKK (nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone) were purchased from Sigma.
4. EMP2 클로닝4. EMP2 Cloning
EMP2의 발현을 증가시키는 물질을 탐색하기 위하여 EMP2의 프로모터를 IMGSB737G122013D (SourceBiosience)로부터 5’-TACTGTTATATGTTGTGACCCTG-3’ (서열번호 1)와 5’-CGCTGGCGGCTGCGCTGGCAGCTG-3’ (서열번호 2) 프라이머로 이용하여 TOPO TA vector로 클로닝하여 이를 pGL2 vector에 연결하여 pEMP2-Luc을 확보하였다.In order to search for substances that increase the expression of EMP2, the promoter of EMP2 from IMGSB737G122013D (SourceBiosience) was used as primers 5'-TACTGTTATATGTTGTGACCCTG-3' (SEQ ID NO: 1) and 5'-CGCTGGCGGCTGCGCTGGCAGCTG-3' (SEQ ID NO: 2) TOPO It was cloned into a TA vector and ligated to the pGL2 vector to obtain pEMP2-Luc.
5. luciferase assay5. luciferase assay
폐암세포 A549에 Lipofectamine 2000 으로 transfection 0.2 g 의 pEMP2-Luc과 0.02 g의 pRL-SV40를 포함하는 lipofectamine 2000으로 24시간 동안 transfection 시킨 후에 CSE(1%) 혹은 CSC(10 g/ml) 및 니코틴 혹은 다이오스제닌 및 프로게스테론 등을 48 h 시간 처리 하였다. 세포 추출물을 만들어 luciferase 활성을 측정하는데 firefly luciferase 신호는 renilla luciferase 신호로 normalize하였다.Lung cancer cells A549 transfection with Lipofectamine 2000 After transfection with lipofectamine 2000 containing 0.2 g of pEMP2-Luc and 0.02 g of pRL-SV40 for 24 hours, CSE (1%) or CSC (10 g/ml) and nicotine or Eosgenin and progesterone were treated for 48 h. To measure luciferase activity by making a cell extract, the firefly luciferase signal was normalized to the renilla luciferase signal.
6. Western blot6. Western blot
본 발명에서는 EMP2, NF-kB, p-NF-kB의 수준을 평가하기 위해 A549 폐암세포주를 배양하여 세포추출물을 제조하여 Western blot 방법으로 분석하는데 사용하였다.In the present invention, in order to evaluate the levels of EMP2, NF-kB, and p-NF-kB, the A549 lung cancer cell line was cultured to prepare a cell extract and used for analysis by Western blot method.
실시예 1. EMP2와 바이러스 침투 관련 유전자들의 관련성 평가Example 1. EMP2 and the evaluation of the relationship of virus penetration-related genes
EMP2 유전자가 폐세포에서 바이러스의 감염과 관련성이 있는지 평가하기 위해, EMP2-/- 마우스로부터 MEF(mouse embryonic fibroblast) 세포를 분리하고, RNA를 추출하여 바이러스 침투와 관련된 유전자의 발현 정도를 측정하였다.To evaluate whether the EMP2 gene is related to virus infection in lung cells, MEF (mouse embryonic fibroblast) cells were isolated from EMP2 -/- mice, and RNA was extracted to measure the expression level of genes related to virus penetration.
도 1은 EMP2 결여 조건에서 바이러스의 침투와 관련된 유전자들의 발현 변화를 평가한 그래프이다. 도 1에 나타난 바와 같이, EMP2 유전자가 결여된 마우스 유래의 MEF 세포에서는 바이러스 침투와 관련된 유전자의 발현이 전체적으로 증가하는 것으로 나타났다. 특히, 도 2에 나타난 바와 같이, EMP2 결여 조건에서 2019 신종코로나바이러스의 수용체로 알려진 ACE2 및 DPP4의 발현이 현저하게 증가하는 것으로 나타났다. 도 3은 EMP2의 결여조건에서 2019 신종코로나바이러스의 수용체로 알려진 DPP4의 발현이 증가되는 것을 western blot으로 검증한 결과이다.1 is a graph evaluating the expression change of genes related to the infiltration of the virus in the absence of EMP2 conditions. As shown in FIG. 1 , in MEF cells derived from mice lacking the EMP2 gene, the expression of genes related to virus penetration was overall increased. In particular, as shown in FIG. 2 , it was found that the expression of ACE2 and DPP4, known as receptors for the 2019 novel coronavirus, was significantly increased in the EMP2 absence condition. Figure 3 is the result of verifying by western blot that the expression of DPP4, known as the receptor of the 2019 novel coronavirus, is increased in the absence of EMP2.
상기 결과는 EMP2 유전자의 발현이 감소하면, 바이러스 감염, 특히 2019 신종코로나바이러스의 감염 위험성이 증가한다는 것을 입증한다.The above results demonstrate that when the expression of the EMP2 gene is reduced, the risk of viral infection, especially the 2019 novel coronavirus, increases.
실시예 2. 흡연이 EMP2 발현에 미치는 영향 평가Example 2. Evaluation of the effect of smoking on EMP2 expression
2019 신종코로나바이러스에 감염되어 폐렴 또는 패혈증으로 진단받은 다수의 환자들이 흡연자인 것으로 밝혀진 바 있다. 따라서 흡연에 의한 EMP2의 발현 수준 변화를 측정하여 바이러스 감염 위험 정도를 평가하였다.A number of patients diagnosed with pneumonia or sepsis infected with the 2019 novel coronavirus were found to be smokers. Therefore, by measuring the change in the expression level of EMP2 caused by smoking, the degree of risk of viral infection was evaluated.
도 4은 폐암 세포주에 담배 연기 농축액(cigarette smoke condensates, CSC) 또는 담배 연기 추출물(cigarette smoke extract, CSE) 처리에 따른 EMP2의 발현 변화를 평가한 사진이다. 도 5는 폐암 세포주에 니코틴 처리에 따른 EMP2의 발현 변화를 평가한 사진이다.Figure 4 is a photograph evaluating the expression change of EMP2 according to the treatment of cigarette smoke concentrate (cigarette smoke condensates, CSC) or cigarette smoke extract (CSE) in lung cancer cell lines. 5 is a photograph evaluating the expression change of EMP2 according to nicotine treatment in lung cancer cell lines.
도 4 및 5에 나타난 바와 같이, A549 폐암세포주에 담배 연기 추출물 (cigarette smoke extract), 담배 연기 농축액 (cigarette smoke condensates) 및 니코틴을 처리하자, EMP2의 발현이 현저하게 감소하는 것으로 나타났다.4 and 5, when the A549 lung cancer cell line was treated with cigarette smoke extract, cigarette smoke condensates, and nicotine, the expression of EMP2 was significantly reduced.
상기 결과는 흡연자들에게서 바이러스성 폐렴 또는 패혈증이 발병되는 이유는 흡연을 통해 유입되는 물질이 EMP2의 발현을 억제하기 때문에, 바이러스 침투 관련 수용체의 증가를 통해 바이러스의 감염 위험이 증가하기 때문인 것을 입증한다.The above results demonstrate that the cause of viral pneumonia or sepsis in smokers is that substances introduced through smoking inhibit the expression of EMP2, and that the risk of virus infection increases through an increase in virus penetration-related receptors. .
실시예 3. EMP2 발현 감소가 염증 관련 유전자들에 미치는 영향 평가Example 3. EMP2 expression reduction evaluation of the effect on inflammation-related genes
2019 신종코로나바이러스에 감염되면, 사이토카인 스톰(cytokine storm)이 나타나는 것으로 알려진 바 있으며, 2019 신종코로나바이러스의 감염에 의한 바이러스성 폐렴 또는 패혈증의 발병 위험도와 관련된 EMP2의 발현 감소와 염증 반응의 활성화의 관련성을 확인하였다.It has been known that a cytokine storm appears when infected with the 2019 novel coronavirus, and the decrease in the expression of EMP2 and activation of the inflammatory response associated with the risk of developing viral pneumonia or sepsis caused by infection with the 2019 novel coronavirus. Relevance was confirmed.
EMP2 발현 억제된 MEF 세포에서 NF-kB의 활성화 및 사이토카인(cytokine) 유전자들의 발현 변화 변화를 확인하였다. 도 6는 EMP2 발현 억제에 따른 NF-kB의 활성화 변화를 평가한 사진이다. 도 7은 EMP2 발현 억제에 따른 사이토카인(cytokine) 유전자들의 발현 변화를 평가한 그래프다.Activation of NF-kB and changes in the expression of cytokine genes were confirmed in EMP2 expression-inhibited MEF cells. 6 is a photograph evaluating the activation change of NF-kB according to the suppression of EMP2 expression. 7 is a graph evaluating the expression change of cytokine genes according to the suppression of EMP2 expression.
도 6 및 7에 나타난 바와 같이, EMP2의 발현이 억제된 MEF 세포에서 NF-kB의 활성화 증가하고, 사이토카인 관련 유전자들의 발현이 현저하게 증가하는 것으로 나타났다. 상기 결과는 EMP2의 발현이 감소하면 염증 반응을 활성화한다는 것을 입증한다.As shown in FIGS. 6 and 7 , in MEF cells in which EMP2 expression was suppressed, activation of NF-kB was increased, and the expression of cytokine-related genes was significantly increased. The above results demonstrate that decreased expression of EMP2 activates the inflammatory response.
실시예 4. EMP2 발현 감소가 GPCR에 미치는 영향 평가Example 4. EMP2 expression reduction evaluation of the effect on GPCR
2019 신종코로나바이러스에 감염되면, 미각 및 후각의 소실이 관찰된다고 보고된 바 있으며, 이에 2019 신종코로나바이러스의 감염에 의한 바이러스성 폐렴 또는 패혈증의 발병 위험도와 관련된 EMP2의 발현 감소와 GPCR(G protein coupled receptor)의 기능 이상과의 관련성을 평가하였다.It has been reported that, when infected with the 2019 novel coronavirus, loss of taste and smell is observed, thereby reducing the expression of EMP2 and GPCR (G protein coupled) related to the risk of viral pneumonia or sepsis caused by infection with the 2019 novel coronavirus. The relevance to the dysfunction of the receptor) was evaluated.
도 8은 EMP2 발현 억제에 따른 GPCR(G protein coupled receptor) 관련 유전자들의 발현 변화를 평가한 그래프이다. 도 8에 나타난 바와 같이, EMP2의 발현이 억제된 경우, GPCR(G protein coupled receptor) 관련 유전자들의 발현이 감소되는 것으로 나타났다. 상기 결과는 2019 신종코로나바이러스의 감염에 의한 미각 및 후각의 소실은 EMP2의 발현 감소와 관련이 있음을 시사한다.8 is a graph evaluating the expression change of GPCR (G protein coupled receptor) related genes according to the suppression of EMP2 expression. As shown in FIG. 8 , when the expression of EMP2 was suppressed, the expression of G protein coupled receptor (GPCR) related genes was decreased. The above results suggest that the loss of taste and smell caused by infection with the 2019 novel coronavirus is related to a decrease in the expression of EMP2.
실시예 5. EMP2의 발현 증가 제제 평가Example 5. EMP2 expression increase agent evaluation
EMP2의 발현을 증가시키는 물질을 탐색하기 위한 검색법으로 EMP2 promoter를 luciferase 에 연결하여 EMP2의 발현을 높이는 검색법을 확립하였다. 이를 활용하여 2019 신종코로나바이러스의 치료제로서 EMP2의 발현을 증가시키는 물질을 탐색하였다.As a search method to search for substances that increase the expression of EMP2, a search method to increase the expression of EMP2 was established by linking the EMP2 promoter to luciferase. Using this, a substance that increases the expression of EMP2 as a treatment for the 2019 novel coronavirus was searched for.
도 9은 다양한 천연물의 성분 등을 처리하였을 때 다이오스제닌 처리에 따른 EMP2의 발현 변화를 평가한 그래프이다. 이때 1번 화합물은 amygdalin, 2번 화합물은 baicalin, 3번 화합물은 baicalin, 4번 화합물은 α-mangostin, 5번 화합물은 γ-mangostin, 6번 화합물은 saikosaponin, 7번 화합물은 saikosaponin D, 8번 화합물 은 diosgenin을 나타낸다. 도 10는 프로제스테론 처리에 따른 EMP2의 발현 변화를 평가한 그래프이다. 도 11은 레졸빈 D의 처리에 의해 EMP2의 발현 변화를 평가한 그래프이다. 도 9, 10 및 11에 나타난 바와 같이, 다이오스제닌 및 프로제스테론, 레티노익산, 레졸빈 D의 처리에 따라 EMP2의 발현이 증가하는 것으로 나타났다. 상기 결과는 다이오스제닌 및 프로제스테론이 EMP2의 발현 증진을 통해 바이러스 감염을 억제하는 치료제로서 사용될 수 있음을 입증한다.9 is a graph evaluating the expression change of EMP2 according to the diosgenin treatment when various components of natural products are treated. At this time,
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.
<110> Dongguk University <120> Use of EMP2 for the diagnosis of viral pneumonia or sepsis <130> ADP-2020-0129 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> EMP2-f <400> 1 tactgttata tgttgtgacc ctg 23 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> EMP2-r <400> 2 cgctggcggc tgcgctggca gctg 24 <110> Dongguk University <120> Use of EMP2 for the diagnosis of viral pneumonia or sepsis <130> ADP-2020-0129 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> EMP2-f <400> 1 tactgttata tgttgtgacc ctg 23 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> EMP2-r <400> 2 cgctggcggc tgcgctggca gctg 24
Claims (9)
According to claim 7, wherein the agent for increasing the expression level of the EMP2 protein or a gene encoding it is psychosaponin D (saikosaponin D), diosgenin (diosgenin), progesterone (progesterone), resolvin (resolvin), or retino Iksan (retinoic acid), characterized in that the pharmaceutical composition.
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| KR20160045580A (en) * | 2014-10-17 | 2016-04-27 | 동국대학교 산학협력단 | Lung cancer-related animal model by causing deficiency of EMP2 gene and uses thereof |
| WO2019213020A1 (en) * | 2018-04-30 | 2019-11-07 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Use of epithelial membrane protein 2 (emp2) targeting agents in treating lung disorders |
| KR102113598B1 (en) * | 2020-02-21 | 2020-05-22 | 주식회사 바이오닉스 | Primer sets for detecting corona viruses and using thereof |
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| KR20160045580A (en) * | 2014-10-17 | 2016-04-27 | 동국대학교 산학협력단 | Lung cancer-related animal model by causing deficiency of EMP2 gene and uses thereof |
| WO2019213020A1 (en) * | 2018-04-30 | 2019-11-07 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Use of epithelial membrane protein 2 (emp2) targeting agents in treating lung disorders |
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