京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19565号 / 医博第4072号 / 新制||医||1013(附属図書館) / 32601 / 京都大学大学院医学研究科医学専攻 / (主査)教授 江藤 浩之, 教授 前川 平, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The imidazoline I1 receptor (I1-R) is a novel receptor found primarily in the brain and nervous tissue where it modulates neurotransmission. It is named for its high affinity for compounds with an imidazoline structure such as the anti-hypertensive drugs, clonidine and moxonidine. The imidazoline receptor antisera-selected protein (IRAS) is the putative clone of the I1-R. IRAS has a unique structure, which does not resemble any other receptor protein. IRAS is present throughout the body with highest levels in the brain. There is a growing body of research examining the physiological roles of IRAS as an I1-R, in cell survival, migration and protein trafficking. However, there is little research into its neuronal functions. IRAS interacts with other membrane receptors: the mouse homologue of IRAS reorganises the actin cytoskeleton through interaction with the α5β1 fibronectin receptor. IRAS also binds insulin receptor substrate 4 and enhances insulin-induced extracellular signal-regulated kinase1/2 (ERK1/2) activation. Actin reorganisation and ERK1/2 activation are important for the development of neurites during neuronal differentiation. Therefore, the work described in this thesis aimed to investigate the effects of IRAS on neuronal differentiation. Studies reported in this thesis also aimed to investigate whether IRAS affected ERK1/2 signalling of other receptors involved in neuronal differentiation such as the NGF receptor, TrkA, and lysophospholipid receptors. The above aims were carried out in neuronal model PC12 cells transfected with either IRAS or a vector plasmid. Fluorescence microscopy and Western blotting techniques were used to examine the effect of IRAS on cell morphology and ERK1/2 signalling. The work described in this thesis found that IRAS reorganises the actin cytoskeleton and enhances growth cone development in PC12 cells. This study also shows that IRAS differentially enhances or inhibits NGF-induced PC12 cell differentiation depending on the presence or absence of serum in the media. In full-serum conditions, IRAS enhanced neurite outgrowth and this was accompanied by an increase in ERK1/2 activation. In serum-starved cells, IRAS inhibited neurite outgrowth with similar levels of ERK1/2 activation observed in vector- and IRAS-transfected cells. Finally, studies presented in this thesis found that IRAS enhances lysophosphatidic acid-induced ERK1/2 activation and that IRAS interacting with lysophospholipid receptor agonists present in serum is a potential mechanism by which it enhances NGF-induced ERK1/2 activation in full-serum conditions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345359 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008