HSF 1 Requirements in Extraembryonic Development

小鼠诱导的基因突变为生物学家描述重要生物过程或特定途径中靶向基因破坏的生理作用提供了前所未有的挑战和机遇，这些过程既没有被怀疑也没有被预测到。本研究的长远目标是确定热休克转录因子1 （HSF1）在哺乳动物胚胎外发育中的生理作用，并确定通过操纵涉及HSF1的调控网络来提高子宫内存活和生长的策略。Hsf1-/-敲除小鼠表现出复杂的表型，包括胎盘缺陷，取决于遗传背景的存活率降低但可变，以及生长迟缓。重要的是，我们已经确定HSF1在哺乳动物胎盘功能中的关键作用似乎与它作为应激条件下热休克蛋白基因的主要应激诱导反激活因子的特性分离。待验证的主要假设是，在胚胎外发育过程中，调节性热休克因子1 （HSF1）是否通过基于胎盘细胞和母体蜕膜间相互作用的信号通路，控制海绵滋养层的增殖、分化或维持。两种独立和无偏见的方法将被用作发现平台，以识别、分离和表征受HSF1影响的分子途径。微阵列表达谱将用于评估母体和胎儿组织中的差异基因表达（Specific Aim 1），以及在胎盘功能背景下表征的相关信号通路（Specific Aim 2）。另外，基于标记连锁分析的全基因组扫描将使我们能够识别和定位优势修饰位点（Specific Aim 3），该修饰位点在对等基因129 Hsf1敲除小鼠的最严重影响中增加了胎盘性状的存活率（Specific Aim 4）。这些创新方法的主要优势在于，这两个发现平台将产生互补的信息，以计划针对HSF1在特定细胞中的转基因表达和同源菌株的创建的救援策略（specific aim 4）。我们的工作将为HSF1在哺乳动物胎盘功能中的生理作用提供新的见解。我们进一步提出，这些信息可以为HSF1在人类先兆子痫和宫内生长迟缓等疾病的诊断、预后和治疗中的干预提供合理的基础。

Induced genetic mutations in mice have provided unprecedented challenges and opportunities for biologists to characterize the physiological roles of targeted gene disruptions in important biological processes or specific pathways, which were neither suspected not predicted. The broad, long-term objectives of this proposal are to determine the physiological roles that heat shock transcription factor 1 (HSF1) plays in mammalian extra-embryonic development, and to define strategies by which the regulatory network involving HSF1 can be manipulated to enhance in utero survival and growth. Hsf1-/-knockout mice exhibit a complex phenotype including placental defects, reduced but variable survival depending on genetic background, and growth retardation. Importantly, we have determined that the key role(s) for HSF1 in mammalian placental function appears to be dissociated from its well-characterized properties as a major stress-inducible transactivator of heat shock protein genes under stressful conditions. The main hypothesis to be tested is whether or not the role played by the regulatory heat shock factor 1 (HSF1), in extra-embryonic development involves the control of the proliferation, differentiation or maintenance of the spongiotrophoblast layer through signaling pathways based on cross-talk between placental cells and maternal decidua. Two independent and unbiased approaches will be used as discovery platforms to identify, isolate, and characterize the molecular pathways influenced by HSF1. Expression profiling by microarrays will used to assess differential gene expression in maternal and fetal tissues (Specific Aim 1), and the relevant signaling pathways to be characterized in the context of placental function (Specific Aim 2). Separately, whole genome scanning based on marker linkage analyses will enable us to identify and localize the dominant modifier loci (Specific Aim 3) that confer increased survival of the placental traits in the most severely affect to isogenic 129, Hsf1 knockout mice (Specific aim 4). The major strength of these innovative approaches is that both discovery platforms will yield complementary information to plan rescue strategies aimed at transgenic expression HSF1 in specific cells and the creation of congenic strains (Specific aim 4). Our work will provide new insights about the physiological roles of HSF1 in mammalian placental function. We further propose such information can constitute a rational basis to interventions involving HSF1 in the diagnosis, prognosis, and therapy for conditions such as pre-eclampsia and intrauterine growth retardation in humans.