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探討在神經退化性疾病中調控核醣核酸結合蛋白MBNL2表現之機轉

為了解決ap lateral醫學中文的問題，作者王李馨 這樣論述：

中文摘要 iAbstract iiContents iiiIntroduction 1Myotonic dystrophy type 1 (DM1) 1Cerebral involvement of adult-onset DM1 2Genetic basis of DM1 4Molecular mechanism in DM1 4Mouse models of DM1 with expression of CUG repeats 6RNA-binding protein: Muscleblind-like (MBNL) family

8MBNL1 and MBNL2 knockout mice 9Calcium-dependent cysteine protease: Calpain 11Calpain-1 and -2 11Calpain-1 and -2 deficient mice 12Calpain-1 and -2 in neurodegeneration 13Alzheimer’s disease (AD) 14Disease stages of AD 14Clinical presentations of AD 15Brain atrophy of AD

15Two pathological hallmarks of AD 16The aims of the study 20Materials and methods 211. Animals 212. Primary hippocampal neuron culture, drug treatment, virus infection and transfection 213. Cell culture and transient transfection 234. Total protein extraction and sub

cellular fractionation 245. Immunoprecipitation (IP) 256. Immunoblotting analysis 257. RNA preparation, RT-PCR and splicing analysis 268. Immunofluorescence staining and immunohistochemistry 279. Quantification of fluorescent images of brain sections 2910. Quantif

ication of fluorescent images of neurons 3011. Antibodies 3012. Plasmids 3113. Statistical analysis 31Results 331. Characterize the role of MBNL2 in neuronal maturation1.1. MBNL2 is expressed postnatally and increased as neuronal maturation 331.2. MBNL2 expression

is required for promoting adult pattern of RNA processingand neuronal differentiation 342. Determine how neurodegenerative conditions reduce MBNL2 expression2.1. Glutamate-induced excitotoxicity reduces MBNL2 protein expression viaNMDAR activation 352.2. NMDAR-mediated Calpain-2 acti

vation causes MBNL2 protein degradation 362.3. Calcium-dependent nuclear translocation of CAPN2 is associated with reducedMBNL2 expression 382.4. Dysregulated calcium homeostasis reduces MBNL2 expression 392.5. Enhanced nuclear translocation of CAPN2 occurs in the EpA960/CamKII-Cre

brain 402.6. Enhanced nuclear translocation of CAPN2 in neurodegeneration recapitulates thefetal developmental pattern 413. Explore the possibility of the reduced MBNL2 expression associated re-induced fetalpattern of RNA processing as a common feature among neurodegenerative disorders3.

1. Enhanced nuclear translocation of CAPN2, reduced MBNL2 expression and associated aberrant MBNL2-regulated alternative splicing in the degenerative brains of AD 41Discussion 44Perspective 48References 49List of figuresFigure 1. MBNL2 is expressed postnatally and increased with bra

in maturation 64Figure 2. MBNL2 is expressed in the more differentiated cells during hippocampusmaturation 65Figure 3. MBNL2 is expressed ubiquitously in the adult mouse brain 66Figure 4. MBNL2 is expressed in the neurons, oligodendrocytes and astrocytes 67Figure 5. The knockdown

efficiency of MBNL2 shRNAs in cultured neurons 68Figure 6. The alternative splicing and polyadenylation of MBNL2 targets show a fetal to adult transition during neuronal differentiation 70Figure 7. MBNL2 depletion disrupts the developmental RNA processing transition in cultured neurons

71Figure 8. MBNL2 depletion impairs dendrite maturation in cultured neurons 72Figure 9. Glutamate treatment induces excitotoxicity in mature cultured neurons showing condensed nucleus 74Figure 10. Glutamate-induced excitotoxicity reduces MBNL2 protein level in mature cultured neurons 75

Figure 11. Glutamate reduces MBNL2 level via NMDAR activation in cultured neurons 77Figure 12. NMDAR-mediated MBNL2 reduction is calcium dependent 78Figure 13. The alternative splicing and polyadenylation of MBNL2 targets are disrupted in neurons treated with glutamate or NMDA 79Figure 14.

MBNL2 mRNA level is unchanged in cultured neurons treated with glutamate or NMDA 81Figure 15. MBNL2 protein is stable in the neurons 82Figure 16. NMDAR signaling-mediated MBNL2 reduction requires calpain activity incultured neurons 83Figure 17. Protein expression of CAPN1 and CAPN2 are alte

red in NMDA-treatedneurons 84Figure 18. MBNL2 binds to both CAPN1 and CAPN22 in HEK293 cells 85Figure 19. Knockdown efficiency of CAPN1 or CAPN2 shRNAs in neurons 86Figure 20. NMDAR-mediated calpain-2 activation causes MBNL2 degradation inneurons 87Figure 21. Depletion of CAPN2 preserves

MBNL2-regulated alternative splicing andpolyadenylation in neurons upon NMDA treatment 88Figure 22. CAPN2 is predominantly expressed in the cytoplasm of mature neurons 90Figure 23. NMDA treatment induces the nuclear translocation of CAPN2 in neurons 91Figure 24. NMDAR-mediated MBNL2 reduct

ion requires calpain-2 expression in thenucleus and cytoplasm of neurons 92Figure 25. NMDA-induced nuclear translocation of CAPN2 requires calcium 93Figure 26. Nuclear translocation of CAPN2 involves in MBNL2 degradation 94Figure 27. Dysregulated calcium homeostasis induces the nuclear tran

slocation of CAPN2 and reduced MBNL2 expression in neurons 95Figure 28. CAPN2 depletion preserves MBNL2 expression in the neurons with dysregulated calcium homeostasis 96Figure 29. Effect of CAPN2 depletion on the RNA processing pattern of MBNL2 targets in A23187-treated neurons 97Figure 30

. CAPN2 nuclear translocation is occurred in the EpA960/CaMKII-Cre mouse brains 98Figure 31. Nuclear-to-cytoplasmic distribution of CAPN2 during neuronal differentiation 99Figure 32. Nuclear translocation of CAPN2 occurs in the APP/PS1 and THY-Tau22brains 100Figure 33. Reduced MBNL2 express

ion in the APP/PS1 and THY-Tau22 brains 101Figure 34. Aberrant MBNL2-regulated alternative splicing in the APP/PS1 and THY-Tau22 brains 102

探討克雷白氏肺炎桿菌CG43之大毒力質體pLVPK對第三型纖毛表現的影響

為了解決ap lateral醫學中文的問題，作者江柏毅 這樣論述：

克雷白氏肺炎桿菌CG43是一分離自糖尿病患肝膿瘍的菌株，帶有一大毒力質體pLVPK。第三型纖毛是克雷白氏肺炎桿菌主要的黏附因子，也是決定其形成生物膜的必要因子，已知Fur-Fe+2、c-di-GMP及H-NS可正向調控第三型纖毛的表現。除了莢膜多醣生成的調控蛋白基因rmpA及rmpA2，攝鐵系統基因iucABCD-iutA、iroBCDN、fepBC及fecIRA外，pLVPK還帶有可轉譯為c-di-GMP環化酶的LV144及H-NS同源基因hnsp。比較剔除pLVPK後的CG43101和CG43S3101與親本菌株CG43和CG43S3的表現型發現：CG43101和CG43S3101的多醣

莢膜和螯鐵分子的生成量明顯較低，而胞外多醣生成量、抗酸能力沒有明顯改變；相對的，第三型纖毛單位蛋白MrkA及生物膜生成量明顯提升，此顯示pLVPK可能扮演負向調控第三型纖毛表現的角色。為了找出此負向調控的決定因子，首先將pRK415-rmpA及pRK415-rmpA2分別轉型入CG43S3101，結果發現可明顯提升其莢膜多醣生成量，但對MrkA或生物膜的生成量都沒有明顯影響；而比較CG43S3101fur、CG43S3101ryhB和CG43S3101furryhB與CG43S3fur、CG43S3ryhB、CG43S3furryhB後發現：剔除pLVPK使Fur缺乏鐵的活化而

失去抑制小RNA RyhB能力；再比較CG43S3101[pRK415-hnsp]和CG43S3101[pRK415]，結果顯示增加hnsp表現可降低MrkA和生物膜的生成量；最後比較CG43S3101[pRK415-LV144] 與CG43S3101[pRK415]發現LV144的表現也可降低MrkA和生物膜的生成量。綜合上述結果顯示：莢膜多醣生成或Fur-RyhB調控與pLVPK負向影響第三型纖毛的表現可能無關，而H-NSp和LV144可能為pLVPK負向調控第三型纖毛表現的決定因子，其調控機制將待進一步探討。