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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
| dc.contributor.author | Shiann-Tarng Jou | en |
| dc.contributor.author | 周獻堂 | zh_TW |
| dc.date.accessioned | 2021-06-13T03:13:18Z | - |
| dc.date.available | 2007-09-18 | |
| dc.date.copyright | 2006-09-18 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-08-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/31460 | - |
| dc.description.abstract | 我們一系列的研究源起於在尋找、鑑定何者是Jak2作用的下游訊息傳遞蛋白質實驗中，找到已知的PLCgamma1、PLCgamma2及PI3K的adapter subunits p85alpha及catalytic subunit p110delta、SHC和stat 5a/b會與Jak2相結合。
第一部份接著主要是研究PI3K p110delta catalytic subunit的功能。從第一部份的研究得知有許多的receptor tyrosine kinases (例如：Jak2)可以結合並活化PI3Ks (phosphatidylinositol 3-kinases)，但p110delta的角色及功能則尚不清楚。在此部份，我們利用p110delta基因剔除小鼠模式，來研究PI3Ks中催化次單位 (catalytic subunit)的p110delta isoform的角色。結果顯示，此基因剔除小鼠是可以存活的，但會出現許多的缺陷，如成熟的B細胞數目會減少 (這是由於其B細胞在成熟分化過程中，在pro-B-cell的時期時就被阻斷而無法繼續分化)、缺少B1 B細胞、在IgM-receptor-induced Ca2+ flux和B細胞對mitogens的增殖反應 (proliferation response)的功能上會減弱、各種的免疫球蛋白濃度在大體上都會降低、對T cell independent antigens的刺激反應明顯減弱、對T cell-dependent antigens的刺激完全沒有反應的能力及此小鼠的脾臟喪失對抗原刺激 (antigen stimulation)形成Germinal center的能力等等。由上述的實驗結果顯示，PI 3-kinase的p110delta isoform在B細胞發展及功能的訊息傳遞路徑中扮演著無可取代的角色。 第二部份的研究是為了想進一步了解由Jak2-derived peptide pulldown assay實驗中所分離出的PLCgamma2的功能。由之前的研究已顯示磷酸脂肪酶 (Phospholipase) Cgamma2 (PLCgamma2)不只與p110delta同樣在B細胞內的B細胞受體 (B cell receptor)的訊息傳遞路徑中扮演著無可取代的角色，而且在血小板FcRgamma chain的膠原受體 (collage receptor)功能上亦扮演重要角色。此部分的研究結果進一步顯示PLCgamma2也存在於肥大細胞(mast cells)內，而且可被FcepsilonR的cross-linking而活化。雖然PLCgamma2基因剔除的小鼠具有正常的成長和數目的肥大細胞，但是我們仍可發現，PLCgamma2對某些FcepsilonR專一性功能是必要的。另外，PLCgamma2的肥大細胞表現出正常的促細胞分裂蛋白激酶 (Mitogen activated protein kinase)的活化和細胞激素 (cytokine)的製造，但是顯示出由FcepsilonR所調控的Ca2+流動、肌醇三磷酸 (Inositol 1,4,5-trisphosphate)的產生都有減少的現象。 在第一部份研究中已顯示剔除p110delta基因會造成鼠類B細胞免疫功能缺損，而在第三部份的研究則是接續探討p110delta基因在人類B細胞免疫缺乏症所扮演的角色。最近，有些實驗室已建立使用老鼠基因剔除研究的模式，來研究某一未知功能的基因在人類原發性免疫缺乏症 (primary immunodeficiency)致病機轉所扮的角色。我們在第一部份的研究中使用基因剔除研究技術實驗的結果證明，p110delta基因缺乏的小鼠，在B-cell免疫缺乏症 (immunodeficiency)中的表現，跟在BTK基因被剔除的小鼠中的症狀表現非常類似。根據我們的研究數據顯示，p110delta基因是符合屬於B-cell訊息傳遞鏈複合體 (B-cell signal transduction complex)的一份子，它在B-cell發展成熟過程中及其功能扮演無法被取代的角色。在人類原發性B-cell免疫缺乏症 (primary B-cell immunodeficiency)的病童中，大部分的病童在其BTK基因都有突變，使得其在臨床上以X-linked agammaglobulinemia (XLA)疾病來表現。另外，有一些病童在B-cell訊息傳遞鏈複合體的某一基因中是有缺損的。在第三部份的研究中，我們將探查在不明原因B-cell免疫缺乏症的病童中，是否有p110delta基因突變的可能性。在實驗組中有16位病人是來自於15個無血緣關係的家庭，另外有112位正常人當作對照組。我們利用基因的排序分析 (sequence analysis)來確認是否有p110delta基因的多型性和突變。在此研究中我們在實驗組及對照組中，同時都可找到5個single base-pair多型性核苷酸互換 (polymorphic nucleotide exchanges)，但這些核苷酸互換並不會造成臨床上病人的免疫缺乏症。其中有3個核苷酸互換是未曾被發表過的，包括m.953A>G、m.1200C>T及m.1561A>G，其中的m.953A>G及m.1561A>G是會造成氨基酸的改變 (分別會造成N253S 和T456A的變化)。以前未被發表的m.1561A>G的核苷酸互換與已被發表過的m.873A>G的核苷酸互換有完全的 (100％) linkage disequilibrium的關係。另外﹐我們在一位男病童的p110delta基因中找到一個未曾發表過的single base-pair missense突變 (mutation)，此突變m.3256G>A會造成E1021K氨基酸的改變。且此突變與其他5個多型性 (polymorphisms)核苷酸互換不同的地方，在於其家人及對照組中並無發現有相同的突變。Codon 1021是位於p110delta蛋白質高度conservative並具有重要催化功能 (catalytic function)的domain的位置上，當發生此基因突變時，會造成在Codon 1021的位置上原本帶陰電荷的氨基酸E，會被帶陽電荷的氨基酸K所取代，而此種改變可能會使得此蛋白質的folding及功能上造成變化。藉由此病童在臨床上典型的原發性B細胞免疫缺乏症的特徵、其家人及對照組的基因研究以及被取代的氨基酸的排序比對 (alignment comparison)和原子結構 (atomic structure)的分析，可支持此missense的突變很可能與其臨床B細胞免疫缺損表現型是有關聯的。根據以上這些發現可彰顯p110delta不僅在小鼠亦可能在人類免疫缺乏症上也扮演著重要的角色。 我們目前的研究目標為藉由研究分析E1021K突變蛋白的功能，來闡明p110delta基因在人類B細胞免疫缺乏症的致病機轉角色。我們過去及目前的研究主要著重p110delta在淋巴球正常生理免疫訊息傳遞路徑的功能分析。未來的方向將研究p110delta在淋巴球病理病變leukemogenesis訊息傳遞路徑的功能分析。希望透過持續的研究，不僅可更透徹的了解人類淋巴球免疫缺乏症及淋巴性白血病的致病訊息傳遞路徑，更可達到預防醫學與發展有效治療新標的的最後目標。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-13T03:13:18Z (GMT). No. of bitstreams: 1 ntu-95-D84421005-1.pdf: 5961412 bytes, checksum: 4394d889e894527123254c93712f5e11 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | 目錄
一、 中文摘要 1 二、 緒論 3 三、 研究方法與材料 15 四、 結果 24 五、 討論 35 六、 展望 48 七、 論文英文簡述 61 八、 參考文獻 76 九、 圖表 94 十、 附錄--修業期間發表的相關文獻 131 | |
| dc.language.iso | zh-TW | |
| dc.title | PI3K P110δ和PLCγ2在免疫細胞的
功能與訊息傳遞之研究 | zh_TW |
| dc.title | Studies on the Functions and Signal Transduction of PI3K P110δ and PLCγ2 in Immune Effector Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 黃璟隆(Jing-Long Huang),陳瑞華(Ruey-Hwa Chen),謝奇璋(Chi-Chang Shieh),林凱信(Kai-Hsin Lin),田蕙芬(Hwei-Fang Tien) | |
| dc.subject.keyword | PI3K P110δ,PLCγ2,訊息傳遞, | zh_TW |
| dc.subject.keyword | PI3K P110δ,PLCγ2,Signal Transduction, | en |
| dc.relation.page | 131 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-08-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
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