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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
dc.contributor.author | Hsin-Hsiung Chen | en |
dc.contributor.author | 陳信雄 | zh_TW |
dc.date.accessioned | 2021-06-15T13:42:39Z | - |
dc.date.available | 2021-02-26 | |
dc.date.copyright | 2016-02-26 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-12-28 | |
dc.identifier.citation | Part 1:
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51645 | - |
dc.description.abstract | 第一部分:
核受體結合蛋白 (Nuclear receptor interaction protein, NRIP),也可稱作DCAF6及IQWD1,是一個鈣離子 (Calcium) 依賴鈣素 (calmodulin) 結合蛋白。本篇研究中,我們發現 NRIP 是一個新發現的骨骼肌Z-盤(Z-disc)蛋白。經由NRIP基因剔除鼠的產生,我們發現在缺少NRIP後,小鼠會呈現肌力降低,肌肉易疲乏及被動式運動能力降低之性狀。NRIP調控肌肉收縮之機轉主要是藉由位在鈣離子下游之NRIP與鈣素結合後,活化了鈣調神經磷酸酶 (calineurin) 及鈣調蛋白依賴性蛋白質激酶第二型 (calmodulin-dependent protein kinase II ,CaMKII),進而誘導粒線體活性及慢速肌凝蛋白(slow myosin)的產生,也穩定肌漿網 (sarcoplasmic reticulum, SR) 內鈣離子存量之恆定。另外,NRIP基因剔除鼠也表現出肌肉再生延遲之現象。在肌肉受損後 NRIP 的表現量會上升,NRIP的表現上升與肌細胞生成素 (myogenin),肌間線蛋白 (desmin) ,胚胎肌球蛋白重鏈 (embryonic myosin heavy chain, eMyHC) 的表現量上升及肌纖維生成有關。總結,NRIP 是一個新發現的骨骼肌Z-盤 (Z-disc) 蛋白,對肌肉力量的產生及肌肉再生是重要的。 第二部分: 先前結果顯示 NRIP 可透過鈣離子鈣素 (Ca2+/CaM) 之訊息傳遞,進而調控骨骼肌之收縮。在元駿論文中,他發現 NRIP 可維持運動神經元之存活,在冠渝論文中,她進一步利用肌肉專一 NRIP 基因剔除鼠證明運動神經元的退化是因為肌肉缺乏NRIP 蛋白所導致。在本研究中,我們對於NRIP 調控運動神經元存活之機制感到興趣。之前我們已證明,NRIP 基因剔除鼠再生肌肉的肌細胞生成素(myogenin)表現量降低。因此我們推測 NRIP 藉由活化myogenin的表現來維持運動神經元之存活。在基因表現晶片的結果中我們發現,NRIP 缺失再生肌細胞的肌細胞生成素基因的表現下降。在 C2C12 細胞分化過程中,NRIP 和 myogenin 的表現會同時上升並表現在細胞核中。進一步,在 C2C12 細胞分化過程中將 NRIP敲落後,肌纖維的生成與 myogenin 的表現會下降。反之,將 NRIP 大量表現在 C2C12 細胞後,myogenin 的表現會上降。總括上述結果,myogenin 的表現可能需要 NRIP的表現。運動神經元與相連接之肌肉細胞可互相維持其結構及功能之完整,因此,藉由建立治療肌肉退化之藥物篩選模式,對搜尋可能治療肌肉萎縮與肌肉萎縮所導致之神經退化有幫助。我們藉由 CRISPR 方法建構了 NRIP 基因剔除 C2C12 細胞,此細胞具與NRIP敲落C2C12細胞一樣的表現出肌纖維生成能力喪失。因此,NRIP 基因剔除之 C2C12 細胞可能可做為篩選治療肌肉退化藥物之工具。 第三部分: 我們先前已經證明了 NRIP 是一個轉錄輔助因子,可促進雄激素受體 (Androgen receptor, AR) 驅動基因的表現,並且保護 AR 蛋白質使更加穩定。前列腺是一個AR 所影響的器官。因此,在本研究中我們利用 NRIP 基因剃除鼠探討 NRIP 在前列腺發育過程中所扮演的角色。我們的結果發現,在 8 週大的 NRIP 基因剃除鼠的 anterior prostate (AP) 有發育遲緩現象,然而在 ventral prostate (VP) 及 dorsolateral prostate (DLP) 卻沒有此現象。並且AP在 12 週後其發育程度就與正常鼠相同。由於 NRIP 可影響 AR 蛋白分解,因此在 8 周大 NRIP 基因剔除鼠中 AR 的表現量降低到使 AP 無法形成分支。 然而,VP 與 DLP 則可維持一定量的 AR 使其正常發育。我們也發現,在發育遲緩的 AP,K5, K8, 及TUNEL 的表現量增加,顯現出此時期的 AP 正走向分化。 此外, DDB2 是一個 AR 結合蛋白,並且可藉由 CUL4A-DDB1 E3 泛素接連酶複合物分解 AR。 NRIP 像 DDB2 一樣是一個 DCAF 蛋白,擁有可與 DDB1 結合的 DxR 序列。因此NRIP 可能藉由與 DDB2 競爭與 AR 的結合,使得 AR 不被分解。總結,NRIP 可穩定 AR 蛋白質並且在前列腺發育扮演角色。 | zh_TW |
dc.description.abstract | Part 1:
Nuclear receptor interaction protein (NRIP, also known as DCAF6 and IQWD1) is a calcium-dependent calmodulin binding protein (Ca2+/CaM). In this study, we found that NRIP is a novel Z-disc protein in skeletal muscle. NRIP knockout mice (NRIP KO) were generated and found to have reduced muscle strength, susceptibility to fatigue and impaired adaptive exercise performance. The mechanisms of NRIP-regulated muscle contraction depend on NRIP being downstream of calcium signaling, where it stimulates activation of both calcineurin-nuclear factor of activated T-cells, cytoplasmic 1 (CaN-NFATc1) and calmodulin-dependent protein kinase II (CaMKII) through interaction with CaM, resulting in the induction of slow myosin gene expression and mitochondrial activity, and balancing of Ca2+ homeostasis of the internally stored Ca2+ of the sarcoplasmic reticulum. Moreover, NRIP KO mice have delayed regenerative capacity. The amount of NRIP can be enhanced after muscle injury and is responsible for muscle regeneration, coupled with the increased expression of myogenin, desmin and embryonic myosin heavy chain for myogenesis, as well as myotube formation. In conclusion, NRIP is a novel Z-disc protein important for skeletal muscle strength and regenerative capacity. Part 2: Previous results showed that NRIP activates Ca2+/CaM signaling to regulate muscle contraction. In Yuan-Chun thesis, NRIP can support motor-neuron survival. In Kuan-Yu thesis, the muscle-specific NRIP KO mice was generated and further demonstrated that motor neuron degeneration is resulted from NRIP-deleted skeletal muscle. Thereof in this study, we were interested in investigation of what is the mechanism of muscle NRIP-regulating motor neuron survival. We previously demonstrated the myogenin expression is dwonregulated in regenerative muscles of NRIP KO mice. Thus, we hypothesized that NRIP can support motor neuron survival through activating myogenin expression. In C2C12 cells, NRIP and myogenin expression were consistently upregulated during differentiation colocalized in neucleus of C2C12 myotubes. Furthermore, the expression of myogenin and myotube formation was disrupted in NRIP knockdown C2C12 during differentiation; in contrast, force expressing NRIP into C2C12 myoblasts could activate expression of myogenin. Taken together, NRIP may be required for myogenenin expression. Motor neurons and skeletal muscles are requiring each other for maintaining normal structure and functions. To establish drug screening for muscle degeneration could be help for searching the potential therapeutic factors either to muscle dysfunction or muscle-derived motor neuron degeneration. We generated the NRIP KO C2C12 myoblasts by RNA-guided clustered, regularly interspaced, short palindromic repeat (CRISPR)-mediated method. The myogenesis was disrupted in NRIP KO C2C12 myoblasts that is also observed in NRIP silenced C2C12 myoblasts. Thus, the NRIP-deleted C2C12 myoblasts could be an in vitro model for searching the therapeutic factors on muscle degeneration. Part 3: Previously we demonstrated that NRIP is a transcription coactivator to enhance androgen receptor (AR)-driven gene expression and protects AR protein stability. The prostate development is dependent on AR expression. In this part, we investigate NRIP role in prostate development by NRIP KO mice. Our results show that anterior prostate (AP) of NRIP KO mice develops delay at 8-week but becomes normal at 12 -week in comparison with WT mice; but not ventral lateral prostate (VLP) and dorsal lateral prostate (DLP). Due to NRIP role for AR protein stability, the decreased AR level of AP in NRIP KO mice causes the delay branch formation at 8-week that may reach the threshold for branch differentiation. As to VLP and DLP of NRIP KO mice developed normal as wild type may come from the crucial amount AR in NRIP KO mice is enough for branch formation. K5, K8, TUNEL markers, and Ki67 are highly expressed in delayed-development of AP from NRIP KO mice at 8-week; indicating that the luminal glandular is processing to formation. Additionally, we previously found that DDB2 is AR-interacting protein and can degrade AR via CUL4A-DDB1 E3 ligase complex (Chang et al., 2012). NRIP, like DDB2, is a DCAF and therefore contains the classical double DxR box that is responsible for DDB1 binding to the CUL4A-DDB1 complex. We suggest NRIP protects AR stability by competing with DDB2 for AR binding, but not by competing with DDB1 for recruitment to the AR-DDB2-DDB1-CUL4A complex. In sum, NRIP can stabilize AR protein and play a role in prostate development. | en |
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dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………I
誌謝…………………………………………………………………………………II General Introduction……………………………………………………………..III Contents...................................................................................................................1-4 Part 1 NRIP is newly identified as a Z-disc protein, activating calmodulin signaling for skeletal muscle contraction and regeneration………………………..5 中文摘要……………………………………………………………………………..6 Abstract……………………………………………………………………………....7 Chapter 1……………………………………………………………………………..8 1.1 Introduction……………………………………………………………………...8 1.1.1 The characteristics of nuclear receptor interaction protein (NRIP).………………………8 1.1.2 The Ca2+/CaM signaling and muscle contraction.……………………………………...8 1.1.3 The Ca2+/CaM signaling and muscle regeneration.……………………………………..9 Chapter 2…………………………………………………………………………….11 1.2 Materials and Methods…………………………………………………………11 1.2.1 Generation and genotyping of NRIP KO mice………………………………………..11 1.2.2 In vitro measurement of muscle force……………………………………………….11 1.2.3 Behavioral analysis……………………………………………………………….12 1.2.4 Tissue staining by HE, IHC and IFA assays………………………………………… 12 1.2.5 COX and SDH activities…………………………………………………………..13 1.2.6 Calcium transient measurement…………………………………………………….13 1.2.7 Transmission electron microscopy (TEM) …………………………………………..14 1.2.8 Western blotting………………………………………………………………….14 1.2.9 Real-Time quantitative PCR (RT-qPCR)…………………………………………….15 1.2.10 C2C12 cell culture………………………………………………………………15 1.2.11 Recombinant adenovirus generation and infection…………………………………...16 1.2.12 Muscle regeneration analysis……………………………………………………...16 1.2.13 Statistics……………………………………………………………………….16 Chapter 3…………………………………………………………………………….17 1.3 Results…………………………………………………………………………...17 1.3.1 Decreased NRIP expression in aged mice…………………………..........................17 1.3.2 Generation of NRIP knock-out mic…………………………………………………17 1.3.3 NRIP KO mice have less muscle strength and endurance………………………………18 1.3.4 NRIP KO mice have impaired adaptive exercise performance………………………….20 1.3.5 NRIP affects muscle strength through CaN-NFATc1…………………………………..20 1.3.6 NRIP has an effect on mitochondrial activity………………………………………...21 1.3.7 NRIP stimulates phosphorylation of CaMKII………………………………………...22 1.3.8 NRIP acts downstream of calcium signaling to activate both CaN and CaMKII, through interaction with CaM………………………………………………………………….23 1.3.9 NRIP KO mice have delayed skeletal muscle regeneration………………………….....24 1.3.10 NRIP can induce terminal differentiation and myotube formation during muscle Regeneration…………........................................................................................26 Chapter 4…………………………………………………………………………….28 1.4 Discussion………………………………………………………………………..28 Chapter 5…………………………………………………………………………….33 1.5 Figures and Tables……………………………………………………………...33 Fig. 1. NRIP expression in skeletal muscle is age-dependent………………………………...33 Fig. 2. Generation of NRIP knockout (KO) mice. …………………………………………34 Fig. 3. Exercise performance is decreased in NRIP KO mice in comparison with WT mice . ……35 Fig. 4. NRIP activates the CaN-NFATc1 pathway. ………………………………………...36 Fig. 5. NRIP mediates p-CaMKII and the balance Ca2+ storage in the SR. ……………………37 Fig. 6. NRIP acts downstream of calcium signaling to activate both CaN and CaMKII through interaction with CaM. …………………………………………………………………38 Fig. 7. NRIP KO mice have delayed skeletal muscle regeneration after CTX injury. …………...40 Fig. 8. NRIP regulates muscle myogenesis and myotube formation. …………………………41 Supplementary Fig. S1. The body weight and fertile ability of WT and NRIP KO mice………...43 Supplementary Fig. S2. The location and expression of calcium related factors in muscle tissues...44 Supplementary Fig. S3. The forced expression of NRIP increases CaN and CaMKII activities C2C12 cells were infected with either Ad-NRIP or Ad-GFP (MOI =10) ……………………...45 Supplementary Fig. S4. NRIP expression is enhanced after muscle injury and correlates with desmin ……………………………………………………………………………………..46 Table 1 Primer sequences. ……………………………………………………………...47 Table 2 Antibody lists. ………………………………………………………………...48 Chapter 6…………………………………………………………………………….49 1.6 Reference………………………………………………………………………...49 Part 2 The role of NRIP in α-motor neuron survival……………………………..54 中文摘要……………………………………………………………………………..55 Abstract……………………………………………………………………………...56 Chapter 1…………………….………………………………………………………57 2.1 Introduction……………………………………………………………………..57 2.1.1 Muscle contraction andα-motor neuron (α-MN) ……………………………………...57 2.1.2 Muscle-derived factors involved in motor neuron survival……………………………..57 2.1.3 Role of NRIP in motor neuron survival……………………………………………...58 2.1.4 In vitro drug screening model……………………………………………………...59 Chapter 2…………………………………………………………………………….61 2.2 Materials and Methods…………………………………………………………61 2.2.1 C2C12 cell culture………………………………………………………………..61 2.2.2 Recombinant adenovirus generation and infection……………………………………61 2.2.3 CRISPR methods………………………………………………………………...62 2.2.4 Microarray analysis……………………………………………………………….62 2.2.5 Western blotting………………………………………………………………….63 2.2.6 Real-Time quantitative PCR (RT-qPCR) ……………………………………………63 2.2.7 IHC and IFA assays………………………………………………………………63 2.2.8 COX and SDH activities…………………………………………………………..63 2.2.9 Muscle regeneration analysis………………………………………………………63 Chapter 3…………………………………………………………………………….65 2.3 Results………………………………………………………………..................65 2.3.1 Muscle pathology of muscle-specific NRIP KO mice is similar to global NRIP KO mice….65 2.3.2 NRIP mediates expression of myogenin to activate myogenesis process in C2C12 cells…...66 2.3.3 NRIP enhances the expression of myogenin………………………………………….68 2.3.4 CRISPR-mediated NRIP KO C2C12 myoblasts perform disruption of myogenesis process...69 Chapter 4…………………………………………………………………………….71 2.4 Discussion………………………………………………………………………..71 Chapter 5…………………………………………………………………………….74 2.5 Figures and Tables……………………………………………………………...74 Fig. 1. The number of α-motor neurons in spinal cord from 6-week NRIP knockout (KO) mice and WT mice. ……………………………………………………………………………74 Fig. 2. The expression of slow myosin and mitochondrial activity is decreased in muscle specific NRIP conditional knockout (cKO) mice. ………………………………………………...75 Fig. 3. Heat map of microarray data. …………………………………………………….76 Fig. 4. Differentiation of C2C12 myoblasts is disrupted by depletion of endogenous NRIP and overexpression of CaM binding deficient NRIP…………………………………………...77 Fig. 5. Expression of myogenin is regulated by NRIP. ……………………………………..78 Fig. 6. The myogenesis of WT and NRIP KO C2C12 myoblasts. ……………………………79 Table 1 The NRIP sequences from WT, KO3, KO8, KO12 and KO19 C2C12 cells…………….80 Chapter 6…………………………………………………………………………….81 2.6 References……………………………………………………………………….81 Part 3 The role of NRIP in prostate development………………………………...85 中文摘要…………………………………………………………………………….86 Abstract……………………………………………………………………………...87 Chapter 1…………………………………………………………………………….88 3.1 Introduction……………………………………………………………………..88 3.1.1 Androgen receptor and prostate development………………………………………...88 3.1.2 NRIP and DDB2-mediated AR protein stability………………………………………89 Chapter 2…………………………………………………………………………….91 3.2 Materials and Methods…………………………………………………………91 3.2.1 Cell culture……………………………………………………………………...91 3.2.2 Western blot……………………………………………………………………..91 3.2.3 IHC and IFA assays……………………………………………………………….91 Chapter 3…………………………………………………………………………….92 3.3 Results…………………………………………………………………………...92 3.3.1 Delayed differentiation of the anterior prostate lobe in the NRIP knock out mice…………92 3.3.2 AR is a key factor to cause the delayed development in anterior prostate lobe of NRIP KO mice…………………………………………………………………………….93 3.3.3 The undifferentiated lumen in the anterior prostate lobe of NRIP KO mice at 8 week……...93 Chapter 4…………………………………………………………………………….95 3.4 Discussion………………………………………………………………………..95 Chapter 5…………………………………………………………………………….97 3.5 Figures and Tables………………………………………………………………97 Figure 1. Abnormality in prostate differentiation in the NRIP deficient prostate.……………….97 Figure 2. Expression of AR is down-regulated in NRIP knockout mice.………………………98 Figure 3. The NRIP knockout AP showed the cluster of luminal cell in the lumen and possessed higher apoptotic potential than WT AP. ………………………………………………….99 Supplementary Fig. S1. The HE stain of DLP and VP presents normal morphology in NRIP KO mice compared to WT……………………………………………………………….100 Supplementary Fig. S2. The apoptotic and proliferative potential in DLP and VP from 8-week NRIP KO and WT mice……………………………………………………………………101 Chapter 6………………………………………………………………………….102 3.6 References……………………………………………………………………..102 | |
dc.language.iso | en | |
dc.title | NRIP調控小鼠骨骼肌功能,運動神經存活以及前列腺發育之研究 | zh_TW |
dc.title | NRIP regulates skeletal muscle functions, motor neuron survival and prostate development | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳文彬(Wen-Pin Chen),顏裕庭(Yu-Ting Yan),王培育(Pei-Yu Wang),蔡力凱(Li-Kai Tsai) | |
dc.subject.keyword | 第一部份,核受體結合蛋白,鈣離子依賴鈣素,肌肉收縮,Z-盤,肌肉再生,第二部分,核受體結合蛋白,鈣離子依賴鈣素,運動神經元,肌細胞生成素,基因剔除細胞,第三部分,核受體結合蛋白,前列腺,雄激素受體,蛋白質降解,泛素接連複合物, | zh_TW |
dc.subject.keyword | Part 1,NRIP,calcium-dependent calmodulin,muscle contraction,Z-disc,muscle regeneration,Part 2,NRIP,CaM,motor neuron,myogenin,gene-knockout cell,Part 3,NRIP,Prostate,AR,protein degradation,ubiquitin ligase, | en |
dc.relation.page | 104 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-12-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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