생리활성 저분자 화합물의 발굴과 세포 이미징을 통한 작용 기전의 이해

학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 생물물리 및 화학생물학과, 2019. 2. 박승범.Our body has very sophisticated and complex signaling pathways to maintain homeostasis. Therefore, we could understand growth processes based on the knowledge from researches on biological events and improve the quality of life by the suggestion of disease treatment strategies. Among various approaches to understand new biological events, the chemical biology approaches were used in this researches, especially, discovery of bioactive small molecules and visualization of its mode of action by cellular fluorescence imaging for understanding biological phenomena with various aspects. Two biological systems were covered in this dissertation. First, studies about mechanistic target of Rapamycin complex 1 (mTORC1) regulation via Leucyl-tRNA Synthetase (LRS) and Ras-like GTPase D (RagD) protein-protein interaction was described. Three distinct bioactive small molecules were identified by using target-based screening. New aspects on mTORC1 regulation mechanism via LRS-RagD interaction were inferred from the unique activity patterns and biophysical studies of each molecule. Second, the investigation of lipid droplet (LD) reduction mechanism was explained. To identify LD reducing small molecule, image-based LD-monitoring high-contents screening was carried out and the novel LD reduction mechanism study of the hit compound was described. As researches on both mTORC1 regulation via LRS-RagD interaction and LD reduction mechanism are relatively deficient, new results described in this dissertation has greatly contributed to the academic field. Furthermore, it has been confirmed that it is possible to suggest a new disease treatment strategy based on the newly discovered results. Therefore, it is expected to be applied to the medicinal industry as an anti-cancer drug sensitizer and a steatosis attenuating agent.우리 몸은 항상성을 유지하기 위한 매우 정교하고 복잡한 신호전달체계를 갖추고 있다. 그러므로, 생체 내 현상을 조절하는 작용 원리를 연구하면 인체의 생장 방식을 이해할 수 있고, 이를 바탕으로 질병의 치료 전략을 제시함으로써 인류의 삶의 질을 높일 수 있다. 새로운 생명 현상을 탐구하고 이해하기 위한 방법은 여러 가지가 있는데, 본 학위 논문에서는 생리활성 저분자 화합물을 발굴하고, 이 화합물의 작용 기전을 세포 이미징을 통해 시각화하여 다양한 측면에서 새로운 생명 현상을 이해하는 화학생물학적 접근 방법을 이용하였다. 본 학위 논문에는 두 가지의 생명 현상을 연구 하였다. 첫 번째는 세포의 성장을 조절하는 중요한 단백질 복합체인 mechanistic target of Rapamycin complex 1 (mTORC1)을 조절할 수 있는 방법 중 하나인 Leucyl-tRNA Synthetase (LRS)와 Ras-like GTPase D (RagD) 단백질 간의 상호작용에 대한 연구이다. 타겟 기반 스크리닝을 통해 서로 다른 세 가지의 LRS-RagD 상호작용 조절 물질을 발굴하고, 각각의 화합물이 일으키는 독특한 활성 변화 양상과 생물물리학 연구 결과를 바탕으로 LRS-RagD 단백질간 상호작용을 통한 mTORC1를 조절하는 새로운 관점에 대해 기술하고 있다. 두 번째는 지방 대사에 중요한 세포 소기관인 지방 방울을 감소 시키는 방법에 대한 내용이다. 이미징 기반 스크리닝을 수행하여 지방 방울을 감소시키는 저분자 화합물을 발굴하고, 이 화합물의 작용 기전을 탐구하여 기존에 보고되지 않은 지방 방울을 줄이는 새로운 작용 기전을 연구한 내용을 기술하고 있다. LRS-RagD에 의한 mTORC1의 조절 방법과 지방 방울의 감소 작용 기전에 대한 연구는 상대적으로 연구가 미약한 분야이므로 본 학위 논문에 기술된 새로운 연구 결과는 학문적으로 기여하는 바가 크다. 더 나아가, 새로 밝혀진 연구 결과를 바탕으로 새로운 질병 치료 전략을 제시할 수 있는 가능성을 확인하였으므로, 항암 증감제와 지방증 완화제로서의 의약 산업에 적용을 기대하고 있다.Abstract Table of Contents List of Figures List of Table Chapter 1. Introduction 1.1. Chemical biology approaches for comprehension of new biological phenomena 1.1.1. Discovery of bioactive small molecules 1.1.2. Cellular imaging 1.2. mTORC1 pathway and LRS-RagD interaction 1.3. Lipid droplet and autophagy process 1.4. Aims of the dissertation Chapter 2. A new perspective to modulate mTORC1 through LRS-RagD interaction modulators 2.1. Introduction 2.2. Materials and methods 2.3. Results and Discussion 2.3.1. In-house library screening with ELISA-based high-throughput screening system 2.3.2. Possibility to modulate mTORC1 through LRS-RagD perturbation with small molecules 2.3.3. Distinct perturbation of mTORC1 by LRS-RagD inhibition 2.3.4. Different effects on mTORC1 of serum and LRS-RagD interaction 2.3.5. Sensitizing effects to anti-cancer drug 2.4. Conclusion Chapter 3. Discovery of a novel lipid droplet reduction mechanism via lipophagy inducing compound 3.1. Introduction 3.2. Materials and methods 3.3. Results and Discussion 3.3.1. Image-based LD monitoring high-contents screening and Hit compound selection 3.3.2. Selective autophagy, especially lipophagy activation 3.3.3. Ubiquitination of LD surface proteins 3.3.4. Relationship with Endoplasmic reticulum (ER) stress 3.3.5. LD reduction in drug induced steatosis in vitro model 3.4. Conclusion References Abstract in KoreanDocto

Adaptive Channel Estimation Techniques for Massive MIMO Systems

학위논문 (석사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 이정우.Wireless communication systems have been required to transmit a large volume of data more rapidly, and thus wireless communication systems require the utilization of more efficient bandwidth and larger channel capacity. Recently, extending multiple input multiple output (MIMO) system on a very large scale by using a myriad number of antennas at the base station was introduced. This method was so that the frequency efficiency can be greatly increased. Massive MIMO system can maximize frequency efficiency by applying a precoding scheme using the downlink channel state information (CSI) to the transmission data at the base station through the usage of large number of antennas. Time-division duplex (TDD) systems have been mainly studied as they can easily obtain the CSI by using the channel reciprocity between uplink and downlink. In frequency-division duplex (FDD) system, the computational complexity of the downlink channel estimation is proportional to the number of antennas at the base station as the channel reciprocity cannot be used. Therefore, effective channel estimation techniques may have to be studied. In this thesis, novel channel estimation algorithms using some of the adaptive techniques are proposed in a channel model with temporal and spatial correlations. The Kalman filter, known as the optimal channel estimation technique, is impossible to estimate the real-time channel due to matrix operations. When consecutive training signals are transmitted, we proposed time division operation of Kalman filter and normalized least mean square (nLMS) filter to enable channel estimation in real-time. Furthermore, we propose decision feedback nLMS filter which updates the CSI by using correctly decoded data as a training signal during data transmission period. With this approach, the performance can be greatly improved without much increase of the hardware complexity compared to the conventional nLMS filter. Simulation results show the performance of proposed algorithms compared to conventional algorithms in terms of mean square error (MSE) and bit error rate (BER).Abstract........................................................................................................... i Contents........................................................................................................ iii List of Figures.................................................................................................v List of Tables ............................................................................................... vii Chapter 1. Introduction .............................................................................1 Chapter 2. Massive MIMO Systems.........................................................6 2.1. Overview.................................................................................................7 2.2. Achievable rate .......................................................................................8 2.2.1. Point-to-Point MIMO...................................................................8 2.2.2. Multi-User MIMO......................................................................10 2.3. Zero-forcing Precoding Techniques......................................................12 Chapter 3. Channel Estimation Schemes ................................................15 3.1. Adaptive Channel Estimation ...............................................................16 3.1.1. Least Mean Square (LMS) Algorithm .......................................16 3.1.2. Kalman Filter .............................................................................21 3.2. Non-Adaptive Channel Estimation .......................................................26 3.2.1. Least Square (LS) Algorithm.....................................................26 Chapter 4. Practical Channel Estimation for Massive MIMO Systems..29 4.1. System Model .......................................................................................29 4.2. Practical Channel Estimation Techniques.............................................32 4.2.1. Hybrid Channel Estimation........................................................32 4.2.2. Decision Feedback nLMS Channel Estimation..........................36 4.3. Complexity Evaluation .........................................................................38 Chapter 5. Simulation Results.................................................................40 5.1. Simulation Environments......................................................................40 5.2. MSE Performance Evaluation...............................................................42 5.3. BER Performance Evaluation ...............................................................44 5.3.1. Large Temporal Correlation Channel ........................................44 5.3.2. Small Temporal Correlation Channel ........................................46 5.3.3. Delayed Channel Feedback........................................................49 Chapter 6. Conclusions ...........................................................................52 References ....................................................................................................54 초록 ..............................................................................................................57Maste

MONITORING AND ANALYSIS SYSTEM FOR AGGRESSION TRAITS BY MEASURING PSYCHOPHYSIOLOGICAL INDICATOR

심리생리학적 지표 측정을 통한 공격성 분석 및 모니터링 시스템에 대해 개시한다. 심리생리학적 지표 측정을 통한 공격성 분석 및 모니터링 시스템은, 심리학적 공격성 지표 데이터베이스를 생성하고, 측정된 생체 신호와 심리학적 공격성 지표의 상관관계에 대한 분석 결과를 제공하고, 상기 생체 신호와 심리학적 공격성 지표의 상관관계에 기초하여 생체신호 기반의 심리학적 공격성의 하위 특질에 대한 정량화 기준을 생성하고, 상기 생체 신호 기반의 심리학적 공격성을 진단 및 분석하고, 심리학적 공격성 진단 결과 및 공격성 완화 솔루션과 관련된 진단 결과를 제공하는 서버 스테이션과 및 공격성 모니터링 전용 해드셋형 뇌파-심전도 측정 장치를 통해 심전도 및 Fp2 및 F8 채널에서 뇌파를 측정하고, 측정된 뇌파 및 심전도 신호를 상기 서버 스테이션으로 전달하고 상기 서버 스테이션으로부터 진단 결과를 수신하는 유저 스테이션을 포함한다