초록 ▼

○ 한국적 미병 개념 정립: 미병은 현재 질병으로 진단되지 않은 상태로서 이상증상을 호소하거나 검사 상이상소견을 보인 정상B군을 포함하며, 우선적으로 이상증상의 불편함과 회복력이 저하된 대상을 이상증상 기반 미병으로 설정하였고, 문헌연구와 전문가 설문조사를 통해 미병의 기저원인으로 허증(虛證)을 제시하였으며, 이를 관리하기 위해 한의학적 한열과 체질개념을 결합한 관리방안을 마련하였음.

○ 미병의 분류/평가 기준: 본 연구팀이 기확보한 데이터를 통해 1) 체질을 간편하게 진단할 수 있는 도구를 개발하고, 새롭게 추가한 임

○ 한국적 미병 개념 정립: 미병은 현재 질병으로 진단되지 않은 상태로서 이상증상을 호소하거나 검사 상이상소견을 보인 정상B군을 포함하며, 우선적으로 이상증상의 불편함과 회복력이 저하된 대상을 이상증상 기반 미병으로 설정하였고, 문헌연구와 전문가 설문조사를 통해 미병의 기저원인으로 허증(虛證)을 제시하였으며, 이를 관리하기 위해 한의학적 한열과 체질개념을 결합한 관리방안을 마련하였음.

○ 미병의 분류/평가 기준: 본 연구팀이 기확보한 데이터를 통해 1) 체질을 간편하게 진단할 수 있는 도구를 개발하고, 새롭게 추가한 임상데이터를 이용하여 2) 한열을 진단할 수 있는 도구를 확보하였으며, 3) 이상증상 기반의 미병을 분류할 수 있는 지수(index)를 개발하고, 4) 허증과 울증을 평가할 수 있는 도구의 신뢰도와 타당도를 확보하였음.

○ 미병 임상연구 및 뱅크 구축: 1) 피로, 통증, 수면이상 등 대표적인 미병군으로부터 유효한 지표를 탐색하기 위한 임상증례수집, 미병 특성파악을 위한 질적 연구 등 7건의 임상연구와 직장 및 지역코호트 연구를 수행하여, 누적 4985명의 설문임상정보, 기기계측정보와 혈액검사 결과와 유전체의 생물학적정보를 연계하여 KDC를 확충함. 2) 미병 코호트 자료에서 수집한 임상 및 기기 자료를 바탕으로 미병 분류 및 평가에 활용할 수 있는 지표를 확인하였음.

○ 설태미생물을 활용하여 수면장애 연관 생태구조와 관련 구조분석법을 제시하였으며, 수면장애와 연관된 혈액세포 microRNA 1개와 해녀 대상으로 4개의 한열 연관 SNP과 6개의 미병 연관 SNP을 확보하는 한편, 세포모델기반의 간피로를 유도하는 모니터링 벡터 제작을 완료하였음

○ 미병 약물관리기술 개발: 문헌에 근거하여 미병 아형별 처방과 약재를 선정하였으며 후보약물의 동물실험모델에 의한 효능 평가와 기전연구를 통하여 효능을 검증하였고, 성분 프로파일 분석을 통한 표준화 연구를 수행하여 미병의 약물관리기술 개발을 위한 기반을 구축하였음.

○ 미병(고혈압 위험군) 대상 예방관리 정보시스템 개발: 고혈압으로 이환되기 이전의 미병군을 대상으로 고혈압 및 심뇌혈관질환의 예방관리를 위한 한의소재관련 정보제공 목적의 데이터베이스 및 시스템을 구축함.

○ 미병(고혈압 위험군) 대상 침구경락요법 근거 확립: 고혈압 위험군을 대상으로 침구경락요법 임상연구 및 코호트를 통해 혈압강하 효과에 대한 근거를 구축함.

(출처 : 보고서 초록 p.6)

Abstract ▼

IV. Results
1. Define Mibyeong within the context of the modern Korean society
1) After a thorough review of original texts such as the Donguibogamand multiple Chinese publications pertaining to Mibyeong and subhealth, this study discovered that many symptoms and manifestations related to Miby

IV. Results
1. Define Mibyeong within the context of the modern Korean society
1) After a thorough review of original texts such as the Donguibogamand multiple Chinese publications pertaining to Mibyeong and subhealth, this study discovered that many symptoms and manifestations related to Mibyeong are highly associated with deficiency syndromes, which was verified with a questionnaire for Korean medicine doctors.
2) Concepts in Western medicine that are similar to Mibyeong in traditional Korean medicine are high-risk groups and medically unexplained symptoms.
3) In China, Mibyeong is interpreted rather broadly, from a disease-free, healthy state to a state of recovery from a disease. Mibyeong in China comprises about 30 types of symptoms, and varying management measures are suggested according to constitutions and symptoms.
4) In Japan, Mibyeong is considered somewhere between a state of disease (as diagnosed through examinations) and a very healthy state. (The scope of findings to define Mibyeong was suggested in the 2014 Japanese Mibyeong System Conference by defining a “very healthy state” based on the data for “medical checkup” recipients.)
5) The modern concept of Mibyeong shall encompass both 1) individuals who do not have a disease but show abnormal symptoms and 2) individuals who do not have disease or abnormal symptoms but show abnormal findings. A systematic program is required to group individuals who show abnormal symptoms based on their constitutions and symptoms and apply appropriate regimens accordingly.

2. Establish the Korean medicine data center (KDC)
1) To develop and apply a cohort-based clinical trial methodology, a Mibyeong clinical trial protocol was developed to create a workplace-based occupational cohort and a region-based healthy people cohort at Daejeon University.
2) Clinical evidence of Mibyeong research was obtained by collecting clinical cases of Mibyeong and performing seven Mibyeong clinical trials, including a qualitative study to identify the features and valid indicators of Mibyeong, such as fatigue, pain, and sleep disturbance.
3) An extensive database was created with time-series data for 583 subjects, clinical questionnaire data for 4,985 individuals, measurement data (e.g., pulsimeter, inbody test, heart rate variability), blood test results, and genomic biological data. These data were logged at the Korean Medicine Data Center (KDC).
4) KDC eCRF (data management system) was developed for a systematic management of clinical Mibyeong data, and a website was launched to promote active utilization of KDC.

3. Establish the standard for Mibyeong classification
1) early studies, individuals were classified into healthy, Mibyeong, and disease groups based on the definition that Mibyeong “is a state of physical and mental discomfort but not yet a state of disease.”
2) A 21-item Mibyeong classification scale was developed for the seven major Mibyeong symptoms through clinical trials and epidemiological studies. The validity of the classification standard was verified against the existing scales, including quality of life scales (e.g., EQ5D, SF-12).
3) A 15-item cold/heat questionnaire was developed with a focus on the daily symptoms of the Mibyeong state, as opposed to the previous focus on disease symptoms. Its validity and reliability were verified.
4) An online questionnaire was administered to Korean medicine doctors nationwide. The results indicated that Korean medicine doctors frequently differentiate Mibyeong based on deficiency and stagnation syndromes.
Based on a review of the literature, previous studies, and step-wise expert consultation, a 33-item deficiency-stagnation questionnaire was constructed and its preliminary validity was tested.
5) The accuracy of the Mibyeong classification scale was assessed based on an agreement between two Korean medicine experts. A 75% agreement was achieved.

4. Quantitative Mibyeong indicators
1) Regional and workplace cohort data were analyzed to identify significant indicators for different Mibyeong groups.
2) The indicators used for the analyses can be divided into clinical questionnaire indicators and device indicators. Fatigue, health-related quality of life, and heat-cold symptom differentiation scales were used for the clinical indicators. Body composition, pulse wave, and indicators were used for the device indicators.
3) One-way analysis of variance (ANOVA) was performed to identify statistically significant Mibyeong indicators in the Mibyeong groups in the workplace-based cohorts (as of October, 17, 2016) that were classified into “healthy,” “first stage Mibyeong (Mibyeong 1),” and “second stage Mibyeong (Mibyeong 2).” Between-group differences were examined with post-hoc tests.
4) Fatigue, quality of life, and cold-heat pattern scales were found to be significant clinical indicators of Mibyeong. Significant device indicators of Mibyeong were: phage angle (PA), muscle mass, bone mineral content (BMC), and minerals from the body composition analyzer; autonomous nerve activity, stress resistance, and fatigue from the HRV device; and estimated cardiac output (ECO) and estimated stroke volume index (ESI) from the pulsimeter.

5. Biological mechanisms and indicators of Mibyeong
1) of the rDNA v6 region of microbes in the tongue coatings of the sleep disorder group (n=26) and control group (n=25) revealed that microbial ecological structures can be broadly divided into three types. The samples from the sleep disorder group and control group show high frequencies of two of these three types (P value, 0.039)
2) The associations between various blood indices for white tongue coating and ecological structures of microorganisms in tongue coating were analyzed. Indices related to carbohydrate metabolism, such as glucose and amylase, and indices related to leukocytes, such as MCH and MCHC, were found to be significantly associated with microbial clusters (P value < 0.05)
3) Base sequence profiling through NGS of the V6 region of microbial rDNA, which is usually used to analyze microorganisms in tongue coating, is highly susceptible to noise caused by errors. We were able to considerably reduce noise by using primer sets with molecular index tags and optimizing conditions (20–38%).
4) To obtain microRNA associated with sleep disorder in Mibyeong, NGS (16 sleep disorder and 16 control) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) (29 sleep disorder and 40 control) were performed. One microRNA (hsa-miR-01) was found to be significantly associated with sleep disorder, and five target gene binding site SNPs of hsa-miR-01 were found to be highly associated with anemia, reduced immunity, obesity phenotype, and cold-heat/Mibyeong scales, indicating its strong association with metabolic risks as a result of sleep disorder.
5) Whole-genome sequence analysis was performed on five haenyos(traditional Korean female divers) to identify haenyo-specific SNPs (52) against the Korean reference genome. Eleven SNPs were verified through an additional study (on 171 haenyos) to be specific to haenyo, four of which were related to cold-heat, and six were related to Mibyeong.
6) Liver cell differentiation protocol was acquired from dedifferentiated stem cells to study liver fatigue. Differentiation was induced through chemical means using relatively cheap materials.
7) To monitor differentiated liver cells, a reporter vector was fabricated to enhance the efficiency of differentiation. Some promoter and enhancer regions of the alpha-fetoprotein were fused and attached to a green fluorescent protein (GFP).

6. Drug management for Mibyeong
1) Fatigue type and sleep disturbance type animal models were explored by analyzing Chinese subhealth animal studies.
2) Fifteen classic prescriptions and medicinal herbs for the fatigue type and sleep disturbance type of Mibyeong were investigated.
3) Efficacy of 15 candidate medicines on sleep improvement was explored using sleep disturbance animal models to identify medicines with superior efficacy. One medicine was found to have superior efficacy for anti-inflammation.
4) Efficacy of two medicines (1 prescription, 1 single herbal extract) on altering brain cells and improving sleep was verified through an experiment with varying concentrations.
5) Efficacy of two medicines (1 prescription, 1 single herbal extract) on improving muscle fatigue was verified through an experiment with varying concentrations on physical fatigue animal models.
6) The effects of seven medicines (2 prescriptions, 5 single herbal extracts) on improving fatigue and altering brain cells were observed in stress-induced fatigue animal models. One medicine with superior efficacy is currently under assessment.
7) The optimal extraction conditions for Mibyeong candidate drugs in relation to various variables were established and component profiling was performed for optimization. The method of component analysis was validated to obtain standardized information about Mibyeong medicinal materials.

7. Nondrug (acupuncture) management for Mibyeong
1) Blood pressure, blood lipid levels, and obesity, as well as certain lifestyle habits, such as smoking, drinking, sleeping, and stress, must be controlled to prevent hypertension. We built a database for medicinal herbs that are efficacious on these factors as well as a database for combined use of Western and Eastern medicine for hypertension. We also developed an information system utilizing these databases to enable information search by professionals and the general population, for monitoring of hypertension risk factors, and alarm features for hypertension risks.
2) Acupuncture, moxibustion, and qigong therapies for individuals with high risk for hypertension were identified through literature review and expert consultation. The effectiveness of acupuncture and meridian therapy was verified through various study designs with altered cycle, frequency, and controls. Acupuncture, moxibustion, and qigong therapies were found to be effective in reducing blood pressure in individuals with high risk for hypertension. Cohort studies showed that acupuncture has long-term efficacy on high risk groups and its effect on reducing blood pressure varies according to constitution and symptoms.

8. Applications of the study results
1) The results of this project may lead to the development of a management system for Mibyeong patients with abnormal symptoms. Further, as the population of unhealthy people who are not diagnosed with an illness but show abnormal symptoms is on the rise, this may contribute to an increase in clinical demands for Korean traditional medicine.
2) If the association between Mibyeong and diseases is understood more clearly, it will be possible to provide a self-care system that improves people’s health before they develop a disease. Such a system will contribute to improving people’s health in this aging society and will lower healthcare costs for people.
3) China manages Mibyeong on a national level, and Japan invests considerable effort in Mibyeong management among the elderly through conferences and local governments. Hence, if the outcomes of this project are concretized and put to practical use, it will be possible to export our Mibyeong management program to China and Japan, which will increase Korea’s national competitiveness.
4) It will provide individualized information for people with high risks for hypertension and add features that promote self-health management for clinical use.
5)　Acupuncture and meridian therapies that are effective for high risk groups for hypertension will be clinically applicable. It will be possible to predict the effects of certain factors on reducing blood pressure.

(출처 : Summary p.12)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 초록 ... 6
• 요약문 ... 7
• Summary ... 12
• Table of Contents ... 19
• 목차 ... 21
• 제1부 총괄과제 최종보고서 ... 23
• 제1장 과제 개요 ... 24
• I. 현황 ... 25
• II. 과제 간 통합 ... 26
• III. 연구진척도 및 목표달성도 ... 27
• 제2장 연구개요 및 수행결과 ... 29
• I. 연구개발 개요 ... 30
• II. 연구목표, 전략 및 방법 ... 39
• III. 연구내용 및 결과 ... 45
• IV. 연구수행에 따른 문제점 및 개선방향 ... 70
• 제3장 연구성과 및 활용 ... 73
• 제4장 연구개발비 집행현황 ... 75
• 제2부 세부과제 최종보고서 ... 77
• 제1세부 최종보고서 ... 78
• 제1장. 과제 개요 ... 79
• 제2장. 과제 목표 및 성과달성 ... 80
• 제2세부 최종보고서 ... 167
• 제1장. 과제 개요 ... 168
• 제2장. 과제 목표 및 성과달성 ... 169
• 제3세부 최종보고서 ... 209
• 제1장. 과제 개요 ... 210
• 제2장. 과제 목표 및 성과달성 ... 211
• 참고자료 ... 267
• 자료1. 연구개발 실적통계 세부내역 ... 268
• 끝페이지 ... 282