KR102649080B1 - 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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- KR102649080B1 KR102649080B1 KR1020200090156A KR20200090156A KR102649080B1 KR 102649080 B1 KR102649080 B1 KR 102649080B1 KR 1020200090156 A KR1020200090156 A KR 1020200090156A KR 20200090156 A KR20200090156 A KR 20200090156A KR 102649080 B1 KR102649080 B1 KR 102649080B1
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- sepsis
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- viral pneumonia
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Abstract
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 제공한다.The present invention relates to the use of EMP2 for diagnosing viral pneumonia or sepsis. It confirms that reduced expression of EMP2 is related to infection with the 2019 novel coronavirus, and the EMP2 protein or the gene encoding it is used to diagnose viral pneumonia or sepsis. It is provided as a diagnostic marker for sepsis, and an agent that increases the expression level of the EMP2 protein or the gene encoding it is provided as a treatment for pneumonia or sepsis caused by infection with the 2019 novel coronavirus.
Description
본 발명은 EMP2의 바이러스성 폐렴 또는 패혈증의 진단을 위한 용도에 관한 것이다.The present invention relates to the use of EMP2 for 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.Recently, it has been reported that the number of infected people and deaths is increasing due to various respiratory viruses, such as the 2019 novel coronavirus, which originated in Wuhan, China and is spreading worldwide.
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 is an enveloped virus with a single-stranded positive RNA genome and has been isolated from various animals, including humans, since it was first discovered in 1937. Coronaviruses can be divided into four groups, of which α-coronaviruses and β-coronaviruses mainly infect mammals, and γ-coronaviruses and δ-coronaviruses mainly 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 are being conducted on coronavirus infection, the expression of viral receptors present in lung cells is mainly attracting attention as a factor that causes 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 easily infected by the coronavirus, but many people are asymptomatic and are not easily infected or show mild symptoms. It is being studied that these differences in symptoms are also due to differences in the expression of receptors that affect virus invasion. .
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 treatments attack viruses and have the disadvantage of being neutralized by viruses that mutate easily. Due to this problem, in order to overcome infection by viruses, a new method is needed to enable humans, the host of the virus, to resist the virus. Particularly for viruses that cause infection in the alveoli of the respiratory tract, it is important to prevent virus penetration into 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 in lung cells on the risk of coronavirus 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 diagnosing viral pneumonia or sepsis. It confirms that reduced expression of EMP2 is related to infection with the 2019 novel coronavirus, and the EMP2 protein or the gene encoding it is used to diagnose viral pneumonia or sepsis. It is provided as a diagnostic marker for sepsis, and an agent that increases the expression level of the EMP2 protein or the gene encoding it is provided 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 diagnostic biomarker for viral pneumonia or sepsis, including the EMP2 protein or the gene encoding it.
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 diagnosing viral pneumonia or sepsis, comprising as an active ingredient an agent for diagnosing the expression level of the EMP2 protein or the gene encoding it.
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.Additionally, the present invention includes measuring the expression level of EMP2 protein or the gene encoding it in a biological sample isolated from a patient's tissue; And it provides a method of providing information for the diagnosis of viral pneumonia or sepsis, in which it is determined that viral pneumonia is likely to develop if the expression level of the EMP2 protein or the gene encoding it in the sample is lower than that of the normal control group.
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 includes measuring the expression level of EMP2 protein or the gene encoding it in a biological sample isolated from the tissue of the subject; and determining that the agent is for the prevention or treatment of viral pneumonia or sepsis if the expression level of the EMP2 protein or the gene encoding it increases after treatment with the test substance compared to the disease subject not treated with the test substance. Virus comprising a. A method for screening an agent for preventing or treating pneumonitis or sepsis is provided.
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.Additionally, the present invention provides a pharmaceutical composition for preventing or treating viral pneumonia or sepsis, which contains as an active ingredient an agent that increases the expression level of the EMP2 protein or the gene encoding it.
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 reduced expression of EMP2 is related to infection with the 2019 novel coronavirus, the EMP2 protein or the gene encoding it is provided as a diagnostic marker for viral pneumonia or sepsis, and the EMP2 protein or the gene encoding it is provided. Agents that increase the expression level of genes can 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.Figure 1 is a graph evaluating changes in expression of genes related to virus penetration under EMP2-deficient conditions.
Figure 2 is a graph evaluating changes in expression of ACE2 and DPP4, receptors for the 2019 novel coronavirus, under EMP2-deficient conditions.
Figure 3 is a photograph of the expression change of DPP4, a receptor for the 2019 novel coronavirus, analyzed by western blot under EMP2-deficient conditions.
Figure 4 is a photograph evaluating the change in expression of EMP2 according to treatment of lung cancer cell lines with cigarette smoke condensates (CSC) or cigarette smoke extract (CSE).
Figure 5 is a photograph evaluating changes in the expression of EMP2 according to nicotine treatment in lung cancer cell lines.
Figure 6 is a photograph evaluating the change in activation of NF-kB due to inhibition of EMP2 expression.
Figure 7 is a graph evaluating changes in expression of cytokine genes due to inhibition of EMP2 expression.
Figure 8 is a graph evaluating changes in expression of genes related to GPCR (G protein coupled receptor) due to inhibition of EMP2 expression.
Figure 9 is a graph evaluating changes in expression of EMP2 according to diosgenin treatment.
Figure 10 is a graph evaluating changes in EMP2 expression according to progesterone treatment.
Figure 11 is a graph evaluating changes in expression of EMP2 according to 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 are general terms that are currently widely used as much as possible while considering the function in the present invention, but this may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the relevant invention. Therefore, the terms 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 simply the name of the 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 otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless clearly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.
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.The numerical range includes the values defined in the range above. Every maximum numerical limit given throughout this specification includes all lower numerical limits as if the lower numerical limit were explicitly written out. Every minimum numerical limit given throughout this specification includes every higher numerical limit as if such higher numerical limit was clearly written. All numerical limits given throughout this specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limits were clearly written.
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 diagnostic biomarker for viral pneumonia or sepsis, including the EMP2 protein or the gene encoding it.
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 new coronavirus but also viruses that cause infection in 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 diagnosing viral pneumonia or sepsis, comprising as an active ingredient an agent for diagnosing the expression level of the EMP2 protein or the gene encoding it.
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.Additionally, the present invention includes measuring the expression level of EMP2 protein or the gene encoding it in a biological sample isolated from a patient's tissue; And it provides a method of providing information for the diagnosis of viral pneumonia or sepsis, in which it is determined that viral pneumonia is likely to develop if the expression level of the EMP2 protein or the gene encoding it in the sample is lower than that of the normal control group.
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 includes measuring the expression level of EMP2 protein or the gene encoding it in a biological sample isolated from the tissue of the subject; and determining that the agent is for the prevention or treatment of viral pneumonia or sepsis if the expression level of the EMP2 protein or the gene encoding it increases after treatment with the test substance compared to the disease subject not treated with the test substance. Virus comprising a. Provided is a screening method for agents for preventing or treating pneumonitis 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.Additionally, the present invention provides a pharmaceutical composition for preventing or treating viral pneumonia or sepsis, which contains as an active ingredient an agent that increases the expression level of the EMP2 protein or the gene encoding it.
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.Agents that increase the expression level of the EMP2 protein or the gene encoding it include saikosaponin D, diosgenin, progesterone, resolvin, or retinoic acid. However, it is not limited to this.
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, liniment agents, pasta agents, and cataplasma agents.
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 additionally contain pharmaceutically acceptable carriers and diluents for formulation. The pharmaceutically acceptable carriers and diluents include excipients such as starch, sugar, and mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, gelatin, alginate, and polyvinyl chloride. Including, but not limited to, binders such as rolidone, lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone and crospovidone, and surfactants such as polysorbate, cetyl alcohol, and glycerol. No. The pharmaceutically acceptable carrier and diluent may be biologically and physiologically friendly to 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 can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically) depending on the 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 weight, age, gender, health condition, 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, to aid understanding of the present invention, it will be described in detail through experimental examples and examples. However, the following experimental examples and examples only illustrate the content of the present invention and 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 with average knowledge in the art.
<실험예> 실험 재료 및 방법<Experimental example> Experimental materials and methods
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 E13.5 stage embryos from EMP2 -/- mice, and cultured in DMEM medium. Cultured under conditions of 37 o C, 3% O 2 , 5% CO 2 .
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 and 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, RNA seq method was used to evaluate the expression level of specific genes. Specifically, RNA was extracted from cultured EMP2 -/- MEF cells using trizol, etc., and the RNA was sent to Ebiogen for 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.Cigarette smoke extract and cigarette smoke condensates used in the present invention were provided by Professor Lee Moo-yeol of Dongguk University, Tobacco Business Group.
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 was used as primers 5'-TACTGTTATATGTTGTGACCCTG-3' (SEQ ID NO. 1) and 5'-CGCTGGCGGCTGCGCTGGCAGCTG-3' (SEQ ID NO. 2) from IMGSB737G122013D (SourceBiosience) and TOPO It was cloned into a TA vector and linked to 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 were transfected with Lipofectamine 2000. After transfection for 24 hours with lipofectamine 2000 containing 0.2 g of pEMP2-Luc and 0.02 g of pRL-SV40, CSE (1%) or CSC (10 g/ml) and nicotine or Eosgenin and progesterone were treated for 48 h. Cell extracts were prepared to measure luciferase activity, and 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, to evaluate the levels of EMP2, NF-kB, and p-NF-kB, A549 lung cancer cell line was cultured, cell extracts were prepared, and used for analysis by Western blot method.
실시예 1. EMP2와 바이러스 침투 관련 유전자들의 관련성 평가Example 1. Evaluation of the relationship between EMP2 and genes related to virus invasion
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 viral infection in lung cells, mouse embryonic fibroblast (MEF) cells were isolated from EMP2 -/- mice, RNA was extracted, and the expression level of genes related to virus invasion was measured.
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.Figure 1 is a graph evaluating changes in expression of genes related to virus penetration under EMP2-deficient conditions. As shown in Figure 1, in MEF cells derived from mice lacking the EMP2 gene, the expression of genes related to virus invasion was found to increase overall. In particular, as shown in Figure 2, the expression of ACE2 and DPP4, known as receptors for the 2019 novel coronavirus, was found to significantly increase under EMP2-deficient conditions. Figure 3 shows the results of western blot verification that the expression of DPP4, known as the receptor for the 2019 novel coronavirus, is increased under conditions lacking 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 infection with 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.It has been revealed that many patients infected with the 2019 novel coronavirus and diagnosed with pneumonia or sepsis were smokers. Therefore, the risk of viral infection was assessed by measuring changes in the expression level of EMP2 due to smoking.
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 change in expression of EMP2 according to treatment of lung cancer cell lines with cigarette smoke condensates (CSC) or cigarette smoke extract (CSE). Figure 5 is a photograph evaluating changes in the expression 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.As shown in Figures 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 found to be 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 reason why smokers develop viral pneumonia or sepsis is because substances introduced through smoking inhibit the expression of EMP2, increasing the risk of viral infection through an increase in receptors related to viral penetration. .
실시예 3. EMP2 발현 감소가 염증 관련 유전자들에 미치는 영향 평가Example 3. Evaluation of the effect of reduced EMP2 expression 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 is known that a cytokine storm occurs when infected with the 2019 novel coronavirus, and a decrease in the expression of EMP2 and activation of the inflammatory response are associated with the risk of developing viral pneumonia or sepsis due to 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 expression of cytokine genes were confirmed in MEF cells in which EMP2 expression was suppressed. Figure 6 is a photograph evaluating the change in activation of NF-kB due to inhibition of EMP2 expression. Figure 7 is a graph evaluating changes in expression of cytokine genes due to inhibition 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 Figures 6 and 7, the activation of NF-kB increased in MEF cells in which EMP2 expression was suppressed, and the expression of cytokine-related genes was found to significantly increase. The above results demonstrate that decreased expression of EMP2 activates the inflammatory response.
실시예 4. EMP2 발현 감소가 GPCR에 미치는 영향 평가Example 4. Evaluation of the effect of reducing EMP2 expression 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 loss of taste and smell is observed when infected with the 2019 novel coronavirus, and this leads to a decrease in the expression of EMP2 and GPCR (G protein coupled), which are related to the risk of developing viral pneumonia or sepsis due to infection with the 2019 novel coronavirus. The relationship with 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.Figure 8 is a graph evaluating changes in expression of genes related to GPCR (G protein coupled receptor) due to inhibition of EMP2 expression. As shown in Figure 8, when the expression of EMP2 was suppressed, the expression of GPCR (G protein coupled receptor)-related genes was found to be reduced. The above results suggest that loss of taste and smell due to infection with the 2019 novel coronavirus is related to decreased expression of EMP2.
실시예 5. EMP2의 발현 증가 제제 평가Example 5. Evaluation of agents that increase expression of EMP2
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 was established to increase the expression of EMP2 by linking the EMP2 promoter to luciferase. Using this, we searched for substances that increase the expression of EMP2 as a treatment for the 2019 novel coronavirus.
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.Figure 9 is a graph evaluating the change in expression of EMP2 according to diosgenin treatment when various natural product components were treated. At this time, compound 1 is amygdalin, compound 2 is baicalin, compound 3 is baicalin, compound 4 is α-mangostin, compound 5 is γ-mangostin, compound 6 is saikosaponin, compound 7 is saikosaponin D, compound 8 is Compound represents diosgenin. Figure 10 is a graph evaluating changes in EMP2 expression according to progesterone treatment. Figure 11 is a graph evaluating changes in EMP2 expression by treatment with Resolvin D. As shown in Figures 9, 10, and 11, the expression of EMP2 was found to increase according to treatment with diosgenin, progesterone, retinoic acid, and resolvin D. The above results demonstrate that diosgenin and progesterone can be used as therapeutic agents to suppress viral infection through enhancing the expression of EMP2.
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 the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. do. That is, the practical 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)
상기 시료에서 EMP2 단백질 또는 이를 암호화하는 유전자의 발현 수준이 정상 대조군에 비해 낮으면 ACE2의 발현이 증가되어 신종코로나바이러스의 감염 가능성이 높을 것으로 판단하는 바이러스성 폐렴 또는 패혈증의 진단을 위한 정보 제공 방법으로서,
상기 바이러스성 폐렴 또는 패혈증은 코로나바이러스의 수용체인 ACE2 및 DPP4의 발현이 증가되어 발병되는 것을 특징으로 하는 정보 제공 방법.Measuring the expression level of EMP2 protein or the gene encoding it in a biological sample isolated from the patient's tissue; and
As a method of providing information for the diagnosis of viral pneumonia or sepsis, where the expression level of EMP2 protein or the gene encoding it in the sample is lower than that of the normal control, the expression of ACE2 is increased and the possibility of infection with the new coronavirus is judged to be high. ,
A method of providing information, characterized in that the viral pneumonia or sepsis is caused by increased expression of ACE2 and DPP4, receptors for the coronavirus.
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