研究
我不是吗?
像你这样的苍蝇?
难道你不是吗?
像我这样的男人?
——威廉·布莱克《苍蝇
A comparison of the molecular mechanisms governing heart development in vertebrates and 果蝇 揭示了所有主要调控成分的显著保存, 包括信号因子和转录因子. 此外, many of these conserved cardiac regulators are found to be mutated in various types of human congenital heart disease. 在两者心脏发育中涉及的保守基因的鉴定 果蝇 和哺乳动物, and detailed investigations of their functions will thus provide considerable insight into related mechanisms controlling cardiogenesis in vertebrates, 包括人类.
因此，艾哈迈德实验室利用综合基因, 基因组, 以及识别与两者相关的新基因的计算策略 果蝇 哺乳动物的心脏发育, 并对其功能和调控进行了详细的探讨. Our ultimate goal is to arrive at a comprehensive understanding of heart development which incorporates both a systems-level view of the underlying genetic network and detailed examinations of the roles of individual genes.
We also use similar integrated approaches to examine and dissect biological processes involved in the development of other organs besides the heart. 艾哈迈德实验室目前的研究项目包括:
Functional analysis of cardiogenic processes regulated by Forkhead/Fox transcription factors.
At least eight transcription factors (TFs) of the Forkhead/Fox family are required for proper cardiac development in mammals, while mutations in four Fox genes have been linked to human congenital heart defects. 然而, relatively little is known about the molecular mechanisms or the downstream targets by which these Fox-mediated developmental functions are brought about. 我们之前在 果蝇 确定了两个狐狸基因的作用, 朱木和ches -1, in specifying cardiac cell subtypes and number by mediating cardiac progenitor cell divisions, 并决定心脏的命运. We also showed that Fox TF binding sites were significantly enriched in the enhancers of cardiac genes. 集体, these results indicate that these two Fox TFs integrate multiple cardiogenic processes by regulating a large number of downstream target genes, raising the question of what these target genes are and what their individual functions might be during heart development.
Utilizing genome-wide transcription expression profiles of mesodermal cells from wild-type embryos and embryos with appropriate genetic perturbations in the Fox genes, we have identified 963 jumu-regulated and 427 CHES-1-like-regulated target genes. We are now identifying and functionally analyzing the diverse cardiogenic cellular processes mediated by these Fox targets.
Determining the functional roles of regulatory genes implicated in cardiogenesis.
通过结合表达分析, 统计荟萃分析和大规模原位杂交, 我们认为是新奇的 果蝇 regulatory genes expressed in the heart or its precursor, the cardiac mesoderm. 在一个单独的项目中, using machine learning to classify cardiac enhancers based primarily on the transcription factor binding sites of orthologous vertebrate TFs, 我们还确定了 果蝇 TFs调节心脏基因. And a third project by our colleagues identified putative mammalian cardiogenic genes from epigenetic gene expression signatures of mouse and human embryonic stem cells differentiating along the cardiac lineage.
Integrating results from these three distinct projects has enabled us to identify many cardiogenic regulators conserved between 果蝇 和哺乳动物, with their conservation suggesting potentially central roles in heart development. 利用两个 果蝇 as a model system and mammalian stem cells directed to differentiate along the cardiac lineage, we are now examining the functional roles of these conserved regulatory genes in cardiogenesis in greater detail.
Understanding the regulatory processes giving rise to distinct cardiac cell subtypes.
在这两个 果蝇 和哺乳动物, 心脏由许多不同类型的细胞组成, raising the question of how these distinct cardiac cell subtypes are specified and differentiated. Taking advantage of the unique expression profiles and stereotypical metameric positioning of the eight different cardiac cell types in 果蝇 在单细胞分辨率水平, we are investigating the signaling and transcriptional processes that determine their fates.
间质-上皮转化(METs)的检查.
从松散关联的过渡, polarity-lacking mesenchymal cells to planar arrays of tightly-packed epithelial cells characterized by apical-basal polarity plays a critical role not only in mammalian cardiogenesis, but also in hepatogenesis (liver development) and nephrogenesis (kidney development). 我们正在用a学习MET 果蝇 imaginal disc model which exhibits a remarkable conservation of signals with mammalian kidney development.
Investigating the transcriptional integration of multiple cues/inputs in gene regulation.
许多个体基因受到多种线索的调控, 比如性, 节段性身份, 和tissue-specificity. We are exploring how these diverse cues are integrated at a transcriptional level.