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    외상성 λ‡Œμ†μƒκ³Ό κ΄€λ ¨λœ μ‹ κ²½ν‡΄ν–‰μ„±μ§ˆν™˜λ“€μ˜ 쒅합적인 전사체 뢄석 연ꡬ

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    ν•™μœ„λ…Όλ¬Έ (박사) -- μ„œμšΈλŒ€ν•™κ΅ λŒ€ν•™μ› : μ˜κ³ΌλŒ€ν•™ μ˜κ³Όν•™κ³Ό, 2020. 8. 김쒅일.Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease caused by repetitive traumatic brain injury (TBI). CTE is mainly found in atheletes who have a history of repetitive blows to the head while playing contact sports such as boxing, American football and professional wrestling. The symptoms of CTE begin years or even decades following exposure to repetitive blows to the head and include changes in thinking, mood, and behavior. The main symptoms of CTE are headaches, memory loss, aggression, depression and dementia. As with other neurodegenerative diseases, there is no specific treatment of CTE. The definitive diagnosis of CTE can only be dignosed from histology studies of brain tissue from those who are deceased. Moreover, the exact gene regulatory mechanisms of CTE are not fully elucidated until now. To better understand the molecular characteristics of CTE, we performed transcriptome sequencing analysis from the post-mortem human brain samples. In the first part, we characterized common or unique transcriptome signatures of CTE, CTE/AD and AD. It is well known that CTE has common or unique neuropathological features with AD. The common neuropathological features of CTE and AD are deposition of hyperphosphorylated tau and presence of neurofibrillary tangles (NFTs). The distribution patterns of NFTs in CTE differs markedly from that in AD. Accordingly, the common or unique transcriptome signatures of CTE, CTE/AD and AD were illustrated by RNA sequencing analysis of post-mortem human brain samples. Interestingly, synaptic transmission- and memory function-related genes were commonly down-regulated in CTE, CTE/AD and AD. Especially, synaptotagmin family genes were markedly dysregulated in TBI-related disorders. Otherwise, cell adhesion molecules-related genes showed remarkable expression changes in CTE. In the second part, we investigated the mechanism of how traumatic brain injury leads to tauopathy in TBI-related neurodegenerative diseases including CTE and AD. Tauopathies are major pathological hallmarks of TBI-related neurodegenerative diseases including CTE and AD. In CTE, an irregular pattern of accumulation aberrantly phosphorylated tau presents in neurons and astroglia around small blood vessels at sulcal depths. In animal models, brain injury is sufficient to induce tau cleavage, acute and sustained aberrant tau phosphorylation and aggregation. In addition, tau-based PET indicates that the temporal neocortex of most individuals over the age of 65 contain pathogenic tau. However, the underlying molecular pathway which drives the tau mediated neurodegeneration is still enigmatic. We found down-regulation of protein phosphatases (PPs) such as PPP3CA, PPP3CB and PPP3R1 in CTE, CTE/AD and AD. We confirmed the elevation of p-tau is inversely correlated with PPs activity in CTE, CTE/AD and AD using in vitro cell lines and in vivo animal models. The common transcriptome signature of CTE and AD was gene expression changes of synaptic transmission and memory loss. The unique transcriptome feature of CTE was upregulation of cell adhesion molecules (CAMs) -related genes. In addition, alteration of protein phosphatase expression contributes to tauopathy in CTE and AD. These studies provide a comprehensive transcriptional mechanism of TBI-related neurodegenerative diseases and lead to novel diagnostic and therapeutic approaches to the diseases.λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦ (CTE) 은 외상성 λ‡Œμ†μƒ (TBI) 에 μ˜ν•΄ λ‚˜νƒ€λ‚˜λŠ” μ‹ κ²½ν‡΄ν–‰μ„±μ§ˆν™˜μœΌλ‘œ 주둜 λ³΅μ‹±μ„ μˆ˜, λ―Έμ‹μΆ•κ΅¬μ„ μˆ˜, 레슬링 μ„ μˆ˜ λ“±μ—μ„œ λ‚˜νƒ€λ‚œλ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ˜ μ£Όμš” μ¦μƒμœΌλ‘œλŠ” 두톡, 기얡상싀, 곡격성, 무관심, λΆˆμ•ˆ, 우울증 등이 μžˆλ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ€ λ‹€λ₯Έ μ‹ κ²½ν‡΄ν–‰μ„±μ§ˆν™˜κ³Ό λ§ˆμ°¬κ°€μ§€λ‘œ μ•„μ§κΉŒμ§€ νŠΉλ³„ν•œ μΉ˜λ£Œλ²•μ΄ μ—†μœΌλ©°, 사후에 뢀검을 ν†΅ν•΄μ„œλ§Œ 진단이 κ°€λŠ₯ν•˜λ‹€. 그리고 λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ„ μœ λ°œν•˜λŠ” μœ μ „μ  μœ„ν—˜ μš”μΈμ— λŒ€ν•œ 연ꡬ도 아직 λ―Έν‘ν•˜λ‹€. κ·Έλž˜μ„œ, λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ˜ λΆ„μžμœ μ „ν•™μ  νŠΉμ„±μ„ μ’€ 더 μ΄ν•΄ν•˜κΈ° μœ„ν•΄, μš°λ¦¬λŠ” μΈκ°„μ˜ λ‡Œ ν‘œλ³Έμ„ ν™œμš©ν•˜μ—¬ 전사체 뢄석을 μˆ˜ν–‰ν•˜μ˜€λ‹€. 첫번째 μ—°κ΅¬μ—μ„œλŠ”, λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ„ 비ꡐ λΆ„μ„ν•˜μ˜€λ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ€ μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘ (AD) κ³Ό μž„μƒ 양상이 맀우 μœ μ‚¬ν•˜λ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ€ κ³ΌμΈμ‚°ν™”λœ νƒ€μš°λ‹¨λ°±μ§ˆμ΄ μΆ•μ λ˜μ–΄ 있고 μ‹ κ²½μ„Έν¬μ„¬μœ λ§€λ“­ (NFTs) 이 μžˆλ‹€λŠ” 곡톡점이 있으며, μ‹ κ²½μ„Έν¬μ„¬μœ λ§€λ“­μ˜ 뢄포 κ²½ν–₯이 λ‹€λ₯΄λ‹€λŠ” 차이점이 μžˆλ‹€. κ·Έλž˜μ„œ λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ˜ 전사체 비ꡐ뢄석을 톡해 λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ˜ νŠΉμ§•μ„ 보닀 λͺ…ν™•νžˆ 밝히렀고 λ…Έλ ₯ν–ˆλ‹€. ν₯λ―Έλ‘­κ²Œλ„, μ‹œλƒ…μŠ€ 전달과 κΈ°μ–΅ κΈ°λŠ₯에 κ΄€λ ¨λœ μœ μ „μžλ“€μ˜ λ³€ν™”κ°€ λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ˜ κ³΅ν†΅μ μœΌλ‘œ λ‚˜νƒ€λ‚¬μœΌλ©°, κ·Έ μ€‘μ—μ„œλ„ μ‹œλƒ…ν† ν…Œκ·Έλ―Ό 이라고 ν•˜λŠ” μ‹œλƒ…μŠ€μ—μ„œ μ‹ ν˜Έμ „λ‹¬μ— κ΄€μ—¬ν•˜λŠ” μœ μ „μžκ°€ λ‘λ“œλŸ¬μ§€κ²Œ λ³€ν™”ν•˜μ˜€λ‹€. 그리고, 세포뢀착과 κ΄€λ ¨λœ μœ μ „μžμ˜ λ³€ν™”λŠ” λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ—μ„œλ§Œ λ‚˜νƒ€λ‚˜, 이것이 λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ˜ μ°¨μ΄μ μž„μ„ μ•Œ 수 μžˆμ—ˆλ‹€. λ‘λ²ˆμ§Έ μ—°κ΅¬μ—μ„œλŠ”, 외상성 λ‡Œμ†μƒμ΄ μ–΄λ–€ λ©”μ»€λ‹ˆμ¦˜μ— μ˜ν•΄ λ§Œμ„± μ™Έμƒμ„±λ‡Œλ³‘μ¦μœΌλ‘œ μ΄μ–΄μ§€λŠ”μ§€ νƒ€μš° λ‹¨λ°±μ§ˆμ— μ΄ˆμ μ„ 맞좰 μ—°κ΅¬ν•˜μ˜€λ‹€. νƒ€μš°λ³‘μ¦(Tauopathy) 은 λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ„ ν¬ν•¨ν•œ 외상성 λ‡Œμ†μƒκ³Ό κ΄€λ ¨λœ μ‹ κ²½ν‡΄ν–‰μ„±μ§ˆν™˜μ˜ κ°€μž₯ μ£Όμš”ν•œ 병리학적 νŠΉμ§•μ΄λ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦μ—μ„œλŠ” λ‰΄λŸ°κ³Ό 별아ꡐ 세포에 μΈμ‚°ν™”λœ νƒ€μš° λ‹¨λ°±μ§ˆμ΄ λΆˆκ·œμΉ™μ μΈ νŒ¨ν„΄μœΌλ‘œ λΆ„ν¬ν•œλ‹€. μ–‘μ „μžλ°©μΆœ λ‹¨μΈ΅μ΄¬μ˜μˆ λ‘œ 65μ„Έ 이상 μ‚¬λžŒλ“€μ˜ 츑두엽을 κ΄€μ°°ν•œ κ²°κ³Ό, λŒ€λΆ€λΆ„μ˜ μ‚¬λžŒλ“€μ΄ νƒ€μš°λ³‘μ¦μ„ 가지고 μžˆλŠ” κ²ƒμœΌλ‘œ λ‚˜νƒ€λ‚¬λ‹€. κ·ΈλŸ¬λ‚˜, μ–΄λ–€ λΆ„μžμ  λ©”μ»€λ‹ˆμ¦˜μ— μ˜ν•΄ νƒ€μš° λ‹¨λ°±μ§ˆμ΄ μ‹ κ²½ν‡΄ν–‰μ„±μ§ˆν™˜μ„ μΌμœΌν‚€λŠ” 지에 λŒ€ν•΄μ„œλŠ” 아직 λ°ν˜€μ§€μ§€ μ•Šμ•˜λ‹€. κ·Έλž˜μ„œ λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦, μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ˜ μœ μ „μž λ°œν˜„ λ³€ν™”λ₯Ό λΆ„μ„ν•˜μ˜€λ‹€. λ‹¨λ°±μ§ˆ μΈμ‚°κ°€μˆ˜λΆ„ν•΄νš¨μ†Œ (PPs) μœ μ „μžλ“€μ΄ λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦, λ§Œμ„± μ™Έμƒμ„±λ‡Œλ³‘μ¦/μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘ 그리고 μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ—μ„œ κ³΅ν†΅μ μœΌλ‘œ λ³€ν™”ν•˜μ˜€λ‹€. 그리고 생체 μ™Έ 세포와 생체 λ‚΄ 동물 λͺ¨λΈμ„ ν™œμš©ν•˜μ—¬, λ‹¨λ°±μ§ˆ μΈμ‚°κ°€μˆ˜λΆ„ν•΄νš¨μ†Œμ™€ μΈμ‚°ν™”λœ νƒ€μš°λ‹¨λ°±μ§ˆμ΄ λ°˜λŒ€λ‘œ μž‘μš©ν•œλ‹€λŠ” 것을 ν™•μΈν•˜μ˜€λ‹€. λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ˜ 곡톡적인 νŠΉμ§•μ€ μ‹œλƒ…μŠ€ 전달과 κΈ°μ–΅ 상싀에 κ΄€μ—¬ν•˜λŠ” μœ μ „μžμ˜ λ³€ν™”μ˜€μœΌλ©°, λ§Œμ„±μ™Έμƒμ„±λ‡Œ λ³‘μ¦λ§Œμ΄ 가지고 μžˆλŠ” νŠΉμ§•μ€ 세포뢀착과 λ¦¬λ³΄μ†œκ³Ό κ΄€λ ¨λœ μœ μ „μžμ˜ λ³€ν™”μ˜€λ‹€. λ˜ν•œ, λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ—μ„œ νƒ€μš°λ³‘μ¦μ„ μΌμœΌν‚€λŠ” 원인 μœ μ „μžλŠ” λ‹¨λ°±μ§ˆ μΈμ‚°κ°€μˆ˜λΆ„ν•΄νš¨μ†Œμ˜€λ‹€. 이 두 연ꡬλ₯Ό 톡해, λ§Œμ„±μ™Έμƒμ„±λ‡Œλ³‘μ¦κ³Ό μ•ŒμΈ ν•˜μ΄λ¨Έλ³‘μ„ μ’€ 더 이해할 수 μžˆμ—ˆμœΌλ©°, 이λ₯Ό 톡해 μ‹ κ²½ 퇴행성 μ§ˆν™˜λ“€μ˜ μƒˆλ‘œμš΄ 진단 κΈ°μ€€κ³Ό μΉ˜λ£Œλ²•μ„ 찾을 수 μžˆμ„ 것이라고 κΈ°λŒ€ν•œλ‹€.General Introduction 1 Next generation sequencing : State-of-the-art method for genome study 2 Tauopathy: A hallmark of neuropathology 5 Chronic traumatic encephalopathy (CTE) : Background and symptoms 7 Alzheimer's disease and neuropathology 10 Objectives of these studies 12 Part I. Characterization of transcriptome signatures in TBI-related neurodegenerative disorders (CTE, CTE/AD and AD) 14 Abstract 15 Introduction 17 Materials and Methods 21 Results 27 Discussion 69 Part II. Alteration of tauopathy-associated transcriptome signatures and molecular mechanisms in CTE and AD : Impaired protein phosphatase expression 75 Abstract 76 Introduction 78 Materials and Methods 80 Results 86 Discussion 116 General Discussion 119 References 122 Abstract in Korean 135Docto

    Opacity and specificity in optimality theory : a supervisor-assisted model

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    Thesis (master`s)--μ„œμšΈλŒ€ν•™κ΅ λŒ€ν•™μ› :μ˜μ–΄μ˜λ¬Έν•™κ³Ό μ˜μ–΄ν•™μ „κ³΅,2003.Maste
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