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UAE(아랍에미리트연합)의 글로벌 교육 전략 연구
No full textThis research is related with the Global HR Forum 2008-Regional Conference in Dubai conducted by KRIVET, The Korea Economic Daily and Ministry of Education, Science and Technology.
In this research, we introduced the Dubai Model, which has grown as a ‘center of the world’ by producing a big project such as Internet City, Media City and Knowledge Village in Dubai, and the Abu Dhabi Model, which has started the business that focuses on Culture and Education after established the board of ‘Abu Dhabi tourism’ on fall of 2004. In addition, we were looking for implications from the UAE’s educational globalization and knowledge management strategies by examining and comparing the Dubai Education Model and Abu Dhabi Education Model.
병리학적 통증에 대한 마이코락톤의 진통효과 및 알츠하이머병에서의 삼차신경 운동 병리의 특성에 대한 연구
Get PDF학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 뇌인지과학과, 2021. 2. 오석배.감각 및 운동 기능은 신체의 생리적 기능을 유지하는 데 중요한 역할을 한다. 신경학적 장애는 중추 및 말초 신경계에 영향을 미치며 일반적으로 이로 인해 나타나는 감각 및 운동 이상은 신경학적다양한 증상을 유발할 수 있다. 이러한 증상들의 예로는 지각변화, 발작 및 혼란과 같은 정신적 증상과 마비, 운동능력 약화 및 협응력저하와 같은 기능 장애, 감각 이상 및 통증과 같은 감각장애로 나눌 수 있으며 이것을 이해하고 치료하는 것은 임상적으로 중요한 의미를 가진다. 따라서 본 학위 논문에서는 염증이나 신경 손상으로 인하여 발생하는 신경장애로 인하여 생기는 감각이상의 기전을 이해하기 위하여 새로운 진통제 후보 물질인 mycolactone의 진통 효과를 검정하였다. Mycolactone은 Mycobacterium ulcerans에 의해 무통성 궤양을 일으키는 것으로 알려진 박테리아 유래 물질이다. 또한 신경퇴행성 질환에서의 말초감각 및 운동신경의 이상을 연구하기 위해 알츠하이머병의 모델인 5XFAD 마우스에서 안면영역으로 분포하는 뇌신경핵과 저작에 작용하는 근육을 조사하였다.
첫 번째 장에서는 mycolactone의 진통작용을 여러 통증 모델과 감각신경세포에서 연구하였다. 먼저 mycolactone의 진통 효과를 행동실험들을 통하여 조사하였을 때 신경병증과 염증성 통증 모델 마우스에서 기계적 통증 및 높은 온도로 인하여 발생하는 통증에서의 진통작용을 5μM 농도에서 확인하였다. 이러한 mycolactone의 진통 기전을 조사하기 위하여 Dorsal Root Ganglion (DRG) 감각신경세포에서 막전위 변화를 감지하는 염료를 기반으로 하는 세포분석법을 개발하였다. 본 실험을 통하여 세포독성이 없는 용량의 mycolactone이 AT2R을 통해 DRG 신경세포에서 과분극을 유도한다는 것을 증명했으며, 이러한 현상은 알려진 AT2R 리간드들에 의해 영향을 받지 않는 것을 확인하였다. 이러한 결과들은 DRG 신경세포에서 mycolactone의 AT2R 신호 전달 경로를 통한 과분극이 진통효과를 가져올 수 있음을 보여줌과 동시에 새로운 자연유래 진통제의 개발가능성을 보여준다.
두 번째 장에서는 5XFAD 알츠하이머 모델마우스에서 알츠하이머병 환자들에게서 보이는 저작장애와 병리학적 특성을 평가하였다. 본 연구를 통하여 5XFAD 마우스에서 저작효율과 최대 교합력의 감소를 확인하였으나 일반적인 운동 기능에는 큰 변화가 없음을 확인하였다. 더욱이, 다른 저작 관련 신경핵들과 비교하였을 때 삼차운동신경핵 (Vmo)에서Amyloid-β (Aβ)의 위치 특이적 축적과 활성이 증가한 미세교세포의 수 및 세포사멸이 관찰되었다. 또한 저작 관련 조직을 조직학적으로 분석한 결과 다른 안면 또는 설하 핵 신경이 분포하는 근육들에 비해 무게와 근섬유의 크기가 감소한 것을 확인하였다. 이러한 발견은 저작기능의 퇴화가 알츠하이머병의 진행에 관여할 수 있으며 저작기능의 조절이 알츠하이머병의 증상 조절에 잠재적으로 도움이 될 수 있음을 시사한다.
I 장과 II 장의 결과에 따르면 병리학 적 통증 (1 장)과 같은 신경 학적 장애에서 발견되는 말초 이상을 치료 표적으로 삼을 시, 박테리아 유래 물질의 잠재적 진통제로서의 사용가능성을 확인할 수 있다. 또한 알츠하이머 병과 같은 중추 신경 장애 (제 2 장)에 대한 본 연구의 결과는 알츠하이머 병에서 발견되는 삼차 운동계와 저작 기능 장애 발현 사이의 연관성을 제시하였다. 따라서 종합적으로 이 논문은 말초 및 중추 신경계 장애를 이해하는 것에 있어 말초 감각 운동 이상을 연구하는 것이 중요하다는 점을 시사한다.Sensory and motor functions play an important role in maintaining physiological functions of the body. Neurological disorders are defined as disorders that affect the central and peripheral nervous system. As sensory and motor abnormalities are commonly manifested in neurological disorders, it can result in a range of symptoms. Examples of these symptoms can be divided into neurological symptoms such as altered levels of consciousness, seizures and confusion and motor dysfunctions such as paralysis, muscle weakness and poor coordination, as well as sensory dysfunctions such as loss of sensation and pain. To gain understanding on the mechanisms of sensory abnormalities induced by neurological disorders such as neurological pain caused by inflammation or nerve damage, and further validate analgesic effect of potential candidate for novel analgesic compound, I investigated the analgesic property of mycolactone, a bacteria-derived toxin which causes non-painful ulcers. Furthermore, to gain understanding on the mechanisms of motor abnormality, specifically masticatory dysfunction as found in Alzheimers disease (AD), I investigated the cranial nuclei innervating orofacial regions and masticatory muscles in 5XFAD mice as below.
In the first chapter, I assessed the analgesic properties of mycolactone on behavioral models and nociceptive neurons. I first investigated the analgesic property of mycolactone in vivo via acute inflammatory pain model induced by 1% formalin. The thickness of the mycolactone injected hind paw showed significantly less inflammation, as well as, analgesia in nocifensive behavior from the second phase of formalin test. For the investigation of analgesic effect of mycolactone on neuropathic pain, I used the chronic constriction injury (CCI) model. The analgesic effect of mycolactone was found in mechanical threshold after i.t. injection of 5μM mycolactone in a dose-dependent manner. The effective dose of mycolactone (5μM) also showed an analgesic effect in the Hargreaves test. Furthermore, to investigate possible mechanism of analgesic property of mycolactone in vitro, I developed a dedicated medium-throughput cellular assay based on membrane potential changes, using bis-oxonol-voltage sensitive dye loaded Dorsal Root Ganglion (DRG) neurons. I demonstrated that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neurons through AT2R, with this action being unaffected by known ligands of AT2R. Altogether, these results indicate an analgesic property of mycolactone and a possible underlying mechanism through AT2R-dependent signaling pathways in DRG neurons with the potential for development of novel nature-inspired analgesics.
In the second chapter, I have assessed masticatory behavior and pathological hallmarks of AD in 5XFAD mouse. 5XFAD mice showed a decreased masticatory efficiency and maximum biting force, while there was no significant change in general motor function. Moreover, significant accumulation of amyloid-β (Aβ), increased number of active microglia, and cell death in trigeminal motor nucleus (Vmo) were observed compared to other mastication-related nucleuses. Furthermore, mastication-related tissues were histologically analyzed and showed a decreased masseter muscle volume and muscle fiber diameter compared to other facial or hypoglossal nuclei innervating muscles. Taken together, the results suggest that degeneration of masticatory function may be involved in progression of AD and control of masticatory function could potentially benefit the control of AD symptoms.
Following results from chapter I and chapter II suggest that targeting peripheral abnormalities found in neurological disorders such as pathological pain (chapter I) can provide insight on potential use of bacteria derived molecule for treatment intervention. Also, for the central neurological disorder such as AD (chapter II), the outcome of this research proposes the importance of understanding the link between trigeminal motor system and manifestation of masticatory dysfunction found in AD. Thus, altogether, this paper underlies the importance of investigating peripheral sensory-motor abnormalities in understanding of peripheral and central neurological disorders.Abstract 1
Contents 4
List of figures 5
List of tables 7
Background 8
Purpose 18
CHAPTER 1: Mycolactone as a novel analgesic molecule. 19
Abstract. 20
Introduction 22
Materials and methods 25
Results 35
Discussion 59
CHAPTER 2: Aβ accumulation in Vmo contributes to masticatory dysfunction in 5XFAD mice 66
Abstract. 67
Introduction 68
Materials and methods 70
Results 75
Discussion 92
General discussion 95
References 97
국문초록 103Docto
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