课题基金 / 基金详情

项目摘要

项目成果

GUILLERMO C OLIVER的其他基金

相似基金

相关文献

中文摘要
翻译
前脑无裂畸形(HPE)是人类前脑最常见的胚胎畸形, 前脑不完全分裂造成的这种畸形影响了 前索板和前神经外胚层包括不同程度的中线融合和独眼畸形 影响了前脑和脸部各种遗传因素和环境因素有助于病因 关于HPE在人类中,编码同源结构域转录因子的SIX 3基因的突变已经被证实是一种基因突变。 与HPE有关。SIX 3促进HPE的遗传和细胞机制知之甚少。它 突变的SIX 3蛋白是否具有亚型、反型或新型活性仍不清楚。Six3 突变以显性方式引起HPE,但具有可变的表达率和表达性,这一发现 表明S/X3与其他遗传位点相互作用。小鼠中Six 3的功能失活表明, 前神经外胚层中Wnt信号的抑制对于脊椎动物前脑的发育是必不可少的; 然而,S/x3-杂合子小鼠没有表现出任何明显形态学改变。在本申请中,我们 建议采用遗传学、胚胎学和分子学方法相结合的方法来繁殖, 表征小鼠和斑马鱼中的HPE/独眼畸形表型。目的1需要在体内和体外 产生的HPE Six 3突变蛋白的分子和转录表征。目标2将 产生Six 3介导的HPE的斑马鱼和小鼠模型。我们将用这些模型来识别组织 以及受突变体Six 3影响的遗传途径目标3的重点是确定基因的合作 与突变的Six 3在促进HPE中的作用。这些拟议的研究将促进我们对 受HPE-Six 3突变影响的信号通路,最终将提供更多信息, 与人类HPE-SIX 3突变携带者的遗传咨询一起使用, 这些先天缺陷。
英文摘要
Holoprosencephaly (HPE) is the most common embryologic malformation of the forebrain in humans caused by incomplete cleavage of the prosencephalon. This malformation which affects the development of the prechordal plate and anterior neuroectoderm includes various degrees of midline fusion and cyclopia affecting the forebrain and face. Various genetic factors and environmental agents contribute to the etiology of HPE. In humans, mutations in the SIX3 gene encoding a homeodomain transcription factor have been associated with HPE. The genetic and cellular mechanisms of SIX3-promoted HPE are poorly understood. It remains unclear whether mutant SIX3 proteins have hypomorphic, antimorphic, or neomorphic activity. SIX3 mutations cause HPE in a dominant manner but with variable penetrance and expressivity, a finding that suggests that S/X3 interacts with other genetic loci. Functional inactivation of Six3 in mice has shown that repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development; however, S/x3-heterozygous mice did not exhibit any obvious morphologic alteration. In this application, we propose to employ a combination of genetic, embryologic, and molecular methods to reproduce and characterize the HPE/cyclopia phenotype in mouse and zebrafish. Aim 1 entails in vivo and in vitro molecular and transcriptional characterization of the generated HPE Six3 mutant proteins. Aim 2 will generate zebrafish and mouse models of Six3-mediated HPE. We will use these models to identify tissues and'genetic pathways affected by mutant Six3. Aim 3 focuses on the identification of genes that cooperate with mutated Six3 in promoting HPE. These proposed studies will advance our understanding of the signaling pathways affected by HPE-Six3 mutations and, ultimately, will provide additional information to be used with the genetic counseling of human carriers of HPE-SIX3 mutations and decrease the frequency of these birth defects.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
11th Latin American Society for Developmental Biology (LASDB) Conference
Mitochondrial respiration as a regulator of lymphatic cell fate and therapeutic lymphangiogenesis
Functional roles of lymphatics in organogenesis and tissue repair
Functional roles of lymphatics in organogenesis and tissue repair
海外基金