FOLATE-RESPONSIVE DYSGENESIS
叶酸反应性发育不全
基本信息
- 批准号:6166083
- 负责人:
- 金额:$ 26.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-01 至 2005-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The objective of the proposed studies is to demonstrate the
central role of the folate receptor (FR) in regulation of transfer of maternal
folates across the placenta and of normal embryogenesis. Abnormal regulation of
FR may be established as a cause for dysgenesis of the developing embryo, in
particular the production of neural tube defects and abnormalities of neural
crest cells. Since these cells undergo bursts of proliferation, the
FR-regulated transfer of folate to the placenta is essential to their
development. Five specific aims are proposed. First, the PI will determine
whether the expression of FR in mouse neural crest cells correlate with bursts
of cellular proliferation by a) demonstrating effects of arrested proliferation
in conjunction with antifolate methotrexate at 12-hour intervals; and b)
correlating these results with changes in FR expression by immunohistochemistry
and in situ hybridization. Second, the PI will determine whether in vivo folate
deficiency induces up regulation of FR in placenta and tissues on gestation day
17 using folate-deficient or folate-replete diets. Approaches to FR expression
in the placenta and tissues will include Northern and Western blots to study
transcriptional and post-translational events as well as nuclear run-on studies
of transcription of FR. Folate deficiency will be monitored by folate and
homocysteine measurements. Fetal tissues will be evaluated by
immunohistochemistry and in situ hybridization. Third, a series of experiments
are proposed to determine whether sustained quenching of placental FR during
maternal folate deficiency using antisense FR will adversely affect placental
proliferation and result in fetal growth retardation. These studies will use
liposomes engineered to deliver antisense FR cDNA incorporated in a placenta
specific promoter at two time points, gestational days 8 and 16. Fourthly, his
group will determine whether the interaction of a specific human 43-kDa
trans-factor liver protein with the cis-element in the 5'-UTR of FR is
identical in the mouse model. These studies will involve isolation and
purification of the trans-factor protein from mouse placenta and
characterization of its function using specific antibody. They will extend
previous observations that homocysteine (Hcy) is a mediator of the trans - cis
interaction. These experiments will use both gel shift assays with placental
slices and large (500-100 mM) concentrations of Hcy. Fifthly, the group will
measure the interaction of the cis and trans elements in ex vivo mouse fetal
culture. This will be achieved by a complex strategy of molecular cloning of
the mouse trans factor and determining concordance of its expression with FR in
mouse fetal tissues. Also they will evaluate the effect of down-regulation of
FR expression by antisense oligonucleotides to both the cis and the trans
elements.
拟议研究的目的是证明
叶酸受体(FR)在母体转移调节中的核心作用
叶酸穿过胎盘和正常胚胎发生。调节异常
FR 可能被认为是发育胚胎发育不全的一个原因,
特别是神经管缺陷和神经异常的产生
嵴细胞。由于这些细胞经历爆发性增殖,
FR 调节的叶酸向胎盘的转移对于它们的发育至关重要
发展。提出了五个具体目标。首先,PI 将确定
小鼠神经嵴细胞中FR的表达是否与爆发相关
a) 证明增殖抑制的效果
每隔 12 小时与抗叶酸甲氨蝶呤联合使用;和 b)
通过免疫组织化学将这些结果与 FR 表达的变化相关联
和原位杂交。二、PI会判断体内是否含有叶酸
缺乏会导致妊娠当天胎盘和组织中 FR 的上调
17 使用缺乏叶酸或富含叶酸的饮食。 FR 表达方法
胎盘和组织中将包括 Northern 和 Western 印迹进行研究
转录和翻译后事件以及核连续研究
FR 的转录。叶酸缺乏症将通过叶酸和
同型半胱氨酸测量。胎儿组织将通过以下方式进行评估
免疫组织化学和原位杂交。三、一系列实验
建议确定胎盘 FR 是否持续猝灭
母体叶酸缺乏症使用反义FR会对胎盘产生不利影响
增殖并导致胎儿生长迟缓。这些研究将使用
脂质体设计用于传递反义 FR cDNA 并入胎盘
在妊娠第 8 天和第 16 天这两个时间点有特定的启动子。
小组将确定特定人类 43-kDa 的相互作用是否
FR 5'-UTR 中带有顺式元件的反式因子肝蛋白是
与小鼠模型相同。这些研究将涉及隔离和
从小鼠胎盘中纯化反式因子蛋白
使用特异性抗体表征其功能。他们将延长
先前的观察表明同型半胱氨酸 (Hcy) 是反式 - 顺式的介体
相互作用。这些实验将使用胎盘凝胶位移测定
切片和大浓度 (500-100 mM) Hcy。第五,集团将
测量离体小鼠胎儿中顺式和反式元件的相互作用
文化。这将通过复杂的分子克隆策略来实现
小鼠反式因子并确定其表达与 FR 的一致性
小鼠胎儿组织。他们还将评估下调的效果
顺式和反式反义寡核苷酸的 FR 表达
元素。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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