臺灣博碩士論文加值系統

a2腎上腺素接受器廣泛的分佈在中樞神經及周邊神經，在(正)腎上腺素((Nor)epinephrine)之刺激下，a2腎上腺素接受器可經由G蛋白質訊號傳導的路徑引發廣效性的生理反應，由藥理學及分子生物學的研究證實此基因家族有三種亞型，三種亞型基因的存在顯示在活體內每個基因都有其特殊功能。此外，三種基因在不同組織的表現都不同，表示其亞型基因的調控機制也可能不同。為了探討這些問題，所以必須建立一個活體模式可供研究。
為了研究a2C腎上腺素接受器基因表現之調控機制，我們做了Adra2c亞型基因調控區的DNA序列分析並且找出其轉錄起始點。更建立了啟動子-報導基因轉殖小鼠的活體動物模式，藉以分析允許a2C腎上腺素接受器基因表現特定的腦區域。在腦中這種調控a2C腎上腺素接受器基因表現的Adra2c基因調控區的DNA序列已經被確認，其調控機制值得討論。
為了研究a2C腎上腺素接受器基因表現在腦中之區域，更為了瞭解a2c腎上腺素接受器在腦中執行的功能，我們採用了一石二鳥的基因剔除方法去建立□a2C腎上腺素接受器亞型基因缺失的老鼠品系，其細胞內的Adra2c亞型基因，為一個報導基因lacZ及抗藥性基因hprt因同源互換所破壞。這種動物模式提供了另一管道去追蹤a2C腎上腺素接受器空間上及時間上兩者的出現形式，因為在同源基因互換之後，此報導基因因為含有上、下游Adra2c基因完整的調控區，所以取代了□a2C腎上腺素接受器亞型基因而表現。
我們構築了a2C腎上腺素接受器亞型基因，Adra2c，的標的載體。將Adra2c基因標的載體以電穿孔方式送入胚胎幹細胞E14內，在HAT及DTX雙重篩選的方式下，即以南方式轉漬法來挑選及確定已經標的的胚胎幹細胞，將標的胚胎幹細胞以顯微注射入老鼠的囊胚，以產生嵌合小鼠。Adra2c亞型基因缺失的嵌合小鼠與C57BL/6J母鼠配種後已得到Adra2c亞型基因缺失的小鼠。這些Adra2c亞型基因缺失小鼠的表現型及a2C腎上腺素接受器的在腦中之組織分佈，將以多種行為測試與原位X-gal染色方式來找出。

□a2 adrenoceptors are widely expressed in both central and peripheral nervous systems. Upon (Nor)epinephrine stimulation, they can trigger a diverse spectrum of physiological responses via G protein-coupled effector pathways. Converging evidence provided by pharmacololical and molecular cloning studies have confirmed the existence of three subtypes in this family. The existence of these subtype genes would suggest that each may be endowed with particular functional roles in vivo. In addition, regulatory mechanisms must exist to account for the differential expression patterns noted in various tissues. To address these issues, in vivo model systems are required.
In order to study the putative regulation of a2C adrenoceptor expression, we have sequence characterized and mapped the transcription start site of its gene, Adra2c. The promoter-reporter (lacZ) transgenic mice models were established and the expression patterns permissive to selective brain areas were examined. Putative regulatory motifs key to expression control in brain were identified and mechanism discussed.
To define the expression atlas and to explore the functional role of a2C adrenoceptor in brain, we have employed a dual-purpose gene knockout (KO) approach. The established mutant mouse strain is deficient in a2C adrenoceptor subtype, as the subtype gene Adra2c is disrupted by a selection marker (Hprt) and a reporter gene (lacZ). The model will also provide an alternative way to trace the temporal and spatial expression patterns of a2C adrenoceptor, as via homologous recombination, the expression of the reporter gene will then be subjected to the control of the regulatory motifs in it entirety both up- and downstream of Adra2c gene.
We have constructed the targeting vector for Adra2c, the gene encoding a2C adrenoceptor subtype. Electroporation of the targeting vector of Adra2c into embryonic stem cell line (ESC) E14 was carried out. Double selection under HAT (Hprt) and DTX (Diphtheris Toxin A) and genomic Southern blot were used to facilitate the identification and selection of targeted ES clones. Blastocysts microinjections of targeted ES clones were carried out for chimeric mice production. Chimeric males with Adra2c subtype gene disrupted were bred to C57BL/6J females for germline transmission check and Adra2c mutant mouse strain was established. The phenotypic triats of Adra2c mutant mice and the expression pattern of a2C adrenergic receptor in brain are currently under investigation using behavior tasks and in situ X-gal staining respectively.

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