POZ-ZF Transcription Factors in Signal Transduction and Development.

多细胞生物体的发育涉及一系列高度协调和受控的事件，这些事件调节细胞的增殖和分化成具有特定功能的组织和器官。这些事件需要通过一种称为信号转导的现象在细胞之间进行交流，信号转导通常在细胞核中达到顶峰，由被称为转录因子的蛋白质控制的基因表达发生变化。基因表达的这些变化反过来会触发细胞做出反应，要么分裂、分化，要么活动起来，要么死亡。虽然已经确定了几种信号通路来调节脊椎动物早期发育的关键阶段，但这些不同的信号是如何整合起来的，以引发发育过程中所需的特定细胞反应，并确保健康的有活力的有机体/脊椎动物，目前还不清楚。一个独特的转录因子家族(POZ-锌指，POZ-ZF)已经被连接到脊椎动物发育所必需的信号通路。这些转录因子相互作用，调节许多靶基因。来自我的实验室的数据显示，缺乏不同POZ-ZF蛋白的青蛙胚胎表现出明显的早期和晚期发育缺陷。这些观察结果导致了我们的假设，POZ-ZF蛋白是脊椎动物早期发育过程中信号转导的重要下游效应器。由于对POZ-ZF蛋白如何与已建立的信号通路机械联系知之甚少，我们的发现研究计划专注于利用细胞系和非洲爪蛙作为模式生物破译POZ-ZF转录因子在脊椎动物发育中的作用和基本作用机制。非洲爪哇是此类研究的成熟模型系统，因为青蛙价格低廉，胚胎非常容易操作，用于蛋白质敲除和过度表达研究，而且我们研究的哺乳动物POZ-ZF蛋白的非洲爪哇版本非常相似。为了实现我们的研究目标，我们将利用各种尖端和成熟的分子细胞生物学和基因技术，以及功能分析。通过实验将POZ-ZF蛋白与已建立的发育信号通路和形态发生事件联系起来，将为脊椎动物早期发育中信号通路之间的串扰提供新的见解。我们的发现还将增加脊椎动物POZ-ZF蛋白功能的知识库，并显著促进我们对所有脊椎动物共有的基本发育过程的了解和理解。我的探索研究项目旨在培养、指导和培养至少七名具有竞争性研究、批判性思维和沟通能力的高素质人才(3名硕士/博士，3名学士)，这些技能对于在加拿大和国际研发领域成功的职业生涯至关重要。

The development of multicellular organisms involves a highly coordinated and controlled series of events that regulates the proliferation and differentiation of cells into tissues and organs with specific functions. These events require communication between cells via a phenomenon called signal transduction, which often culminates in the nucleus with changes in gene expression controlled by proteins called transcription factors. These changes in gene expression in turn trigger cells to respond and either divide, differentiate, become motile or die. Although several signaling pathways have been identified that regulate the crucial stages of early vertebrate development, it remains unclear how these various signals are integrated to elicit the specific cellular responses needed during development, and to ensure a health viable organism/vertebrate. One unique family of transcription factors (POZ-zinc finger, POZ-ZF) have been linked to signaling pathways that are essential for vertebrate development. These transcription factors interact with each other and regulate numerous target genes. Data from my laboratory revealed that frog embryos lacking different POZ-ZF proteins displayed striking early and late developmental defects. These observations led to our hypothesis that POZ-ZF proteins are important downstream effectors of signaling transduction during early vertebrate development. Since little is known about how POZ-ZF proteins are mechanistically connected to established signaling pathways, our Discovery research program focuses on deciphering "The Role and Basic Mechanisms of Action of POZ-ZF Transcription Factors in Vertebrate Development" using cell lines and the frog Xenopus laevis as a model organism. Xenopus is a proven model system for such studies because frogs are inexpensive, the embryos are very easy to manipulate for protein knockdown and overexpression studies, and the Xenopus versions of the mammalian POZ-ZF proteins we are studying are very similar. To achieve our research goals, we will utilize a variety of cutting-edge and established molecular cell biology and genetic techniques, and functional assays. Experimentally linking POZ-ZF proteins to established developmental signaling pathways and morphogenetic events would provide novel insight on the crosstalk between signaling pathways in early vertebrate development. Our findings would also add to the knowledge base of POZ-ZF protein function in vertebrates, and significantly advance our knowledge and understanding of fundamental developmental processes that are shared by all vertebrates. My Discovery research program is designed to train, mentor and produce at least seven highly qualified personnel (3 MSc/PhD, 3 BSc) with competitive research, critical thinking and communication skills; skills that are essential for successful careers in the Canadian and International Research & Development arena.