标题: 利用实验小鼠模式探讨血管收缩素转化酶(ACE2) 表现调节与肺纤维化有关之分子机转
Studying the Regulatory Elements of Angiotensin Converting Enzyme II (ACE2) and the Molecular Mechanism of ACE2 Regulation on Pulmonary Fibrosis by Experimental Mouse Models
作者: 林志生
LIN CHIH SHENG
国立交通大学生物科技学系(所)
关键字: 肺纤维化;血管收缩素转化酶II;基质金属蛋白酶;动物模式;Pulmonary fibrosis;Angiotensin converting enzyme II;Matrix metalloproteinases;Animal model
公开日期: 2014
摘要: 肺纤维化是一项慢性和复杂的疾病,可由多种原因导致,但大部分患者之病因不明,臨
床上称之为原发性肺纤维化(idiopathic pulmonary fibrosis; IPF)。虽然在肾素-血管收缩素系
统中(renin-angiotensin system; RAS),已知血管收缩素转化酶(angiotensin-converting enzyme;
ACE)/ 血管收缩素II(angiotensin II; Ang II)途径(ACE/Ang II axis)与许多肺部疾病有关,
但在RAS 系统中的另一个ACE 類似酵素,血管收缩素转化酶II (angiotensin-converting enzyme
II; ACE2)却鲜少被探讨,其在包括IPF 的一些肺部疾病中的病理生理机转仍有许多未知。在
RAS 中,ACE2 可将Ang II 转化成血管收缩素1-7(angiotensin 1-7; Ang-(1-7)),而Ang-(1-7)
被认为有拮抗Ang II 的生理功能。在我们过去的研究结果中显示,ACE2/Ang-(1-7) axis 的異
常与心脏组织纤维化病程有关,而此可能经由基质金属蛋白酶(matrix metalloproteinases;
MMPs)与基质金属蛋白酶组织抑制因子(tissue inhibitors of MMPs; TIMPs)的调控失衡有关。
在本计画中,我们将探讨肺部 ACE2 表现调节因子与肺纤维化病程有关之分子机转,以
及MMPs/TIMPs 平衡调控与肺脏组织纤维化的关系。在本计画中,我们针对上述的议题,拟
订五个研究目标:(1) 瞭解肺脏组织中ACE2 表现之特定细胞,探讨ACE2 基因表现的调节
因子,以及一些与肺纤维化病变有关之诱发因子(包括bleomycin、TGF-1、Ang II 及Ang-(1-7))
对于肺组织中特定细胞的ACE2 表现之影响;(2) 建立肺纤维化实验小鼠研究模式,利用ACE2
基因剔除(ACE2-/y)实验小鼠与ACE2 活性控制,探讨ACE2 在肺纤维化病程中扮演的角色;
(3) 探讨在肺纤维化病程中,MMPs 和TIMPs 的表现与活化态样,并研究这些MMPs/TIMPs
的表现调节与ACE2 的相关性;(4) 探讨特定MMPs/TIMPs 的活化剂(activator)和抑制剂
(inhibitor)对于进行中之肺纤维化病程的影响;(5) 筛选调节ACE2 表现可能存在之
microRNAs,印证此特定microRNAs 的表现与抑制是否影响肺纤维化之病程,为肺纤维化病
程控制带來新药物开发之契机。
由于目前 IPF 在臨床上尚无明确有效性的用药,因此急需开发更有效率的治療药物,而
我们的研究将有助于研究者更了解ACE2 表现调节与MMPs/TIMPs 的平衡调控在IPF 病程演
进中所扮演的角色,也提供IPF 在预防或治療上具开发潜能之新标的。
Pulmonary fibrosis is a chronic and complicated disease that can come from many different
causes. In the majority of cases of this disease, the cause is not known, called idiopathic
pulmonary fibrosis (IPF). Although angiotensin converting enzyme (ACE)/angiotensin II (Ang II)
axis in renin-angiotensin system (RAS) has been recognized associated with the development of
several pulmonary diseases, including IPF, much less is known about the function of angiotensin
converting enzyme II (ACE2), an ACEhomologue that converts Ang II to angiotensin 1-7
(Ang-(1-7)), a peptide that exerts actions opposite to those of Ang II. In our previous studies, we
showed that ACE2 dysregulation and unbalanced matrix metalloproteinases (MMPs)/tissue
inhibitors of MMPs (MMPs/TIMPs) are highly associated with the fibrotic damage in
cardiovascular diseases. In this project, we are ambitious to study the regulatory elements of ACE2
and molecular mechanism of ACE2 regulation on pulmonary fibrosis by experimental mouse
model. We also attempt to study the roles of ACE2/Ang-(1-7) axis in pulmonary function and test
the hypothesis that whether part of the anti-fibrotic effects of ACE2/Ang-(1-7) axis is via the
balancing regulation of MMPs/TIMPs?
In the present project, we propose five research goals addressing on the above subjects. (1) We
will explore lung-selective ACE2 and the regulatory elements on ACE2 gene expression in
pulmonary cells, fibroblasts and epithelium cells, treated with the fibrosis-induced factors,
including bleomycin, TGF-1 and angiotensin peptides (Ang II and Ang-(1-7)). (2) The
experimental mouse model of pulmonary fibrosis will be established. The pathophysiological roles
of ACE2 in pulmonary fibrosis will be evaluated by ACE2 knockout (ACE2-/y) mice and via the
administration of ACE2 activators or inhibitors. (3) The expression and activity profiles of MMPs
and TIMPs in the developed pulmonary fibrosis will be assayed. We also attempt to understand the
ACE2 regulation associated with the balanced expression and activity of MMPs/TIMPs. (4) The
experimental mice administrated with MMPs/TIMPs activators or inhibitors will be performed to
study the effects of unbalanced MMPs/TIMPs on the pathogenesis of pulmonary fibrosis. (5) We
attempt to screen the microRNAs that can regulate ACE2 expression at translational level and
investigate crucial roles of the ACE2 microRNAs in the fibrotic process of pulmonary fibrosis.
The results can provide an opportunity of controlling ACE2-microRNAs expression in the therapy
for pulmonary fibrosis. Our studies will be valuable in the understanding of anti-fibrotic effects of
ACE2 expression.
Difficulty in the clinical treatments for IPF represents an enormous clinical challenge in need
of effective therapeutic approaches. The anticipated results of this project will provide new insight
into the pathophysiological processes of IPF. Furthermore, our studies will also illustrate new
potential targets or methods, by the modulation of ACE2 expression, ACE2/Ang-(1-7) axis and/or
balanced MMPs/TIMPs control, for IPF prevention and treatments.
官方说明文件#: NSC101-2313-B009-001-MY3
URI: http://hdl.handle.net/11536/103062
https://www.grb.gov.tw/search/planDetail?id=8125445&docId=433610
显示于类别:Research Plans