HSF 1 Requirements in Extraembryonic Development

小鼠的诱导基因突变为生物学家提供了前所未有的挑战和机遇，以表征重要生物过程或特定途径中靶向基因破坏的生理作用，这既不是怀疑也不是预测。 广泛的，长期的目标，这项建议是确定的生理作用，热休克转录因子1（HSF 1）在哺乳动物胚胎外发育中发挥作用，并确定策略，其中涉及HSF 1的监管网络可以被操纵，以提高在子宫内的生存和生长。 hsf 1-/-基因敲除小鼠表现出复杂的表型，包括胎盘缺陷，减少但可变的生存取决于遗传背景，和生长迟缓。 重要的是，我们已经确定，HSF 1在哺乳动物胎盘功能中的关键作用似乎与其在应激条件下作为热休克蛋白基因的主要应激诱导型反式激活因子的充分表征的性质无关。 待检验的主要假设是调节性热休克因子1（HSF 1）在胚胎外发育中所起的作用是否涉及通过基于胎盘细胞和母体蜕膜之间的串扰的信号传导途径来控制海绵滋养层的增殖、分化或维持。 两个独立和公正的方法将被用作发现平台，以确定，分离和表征受HSF 1影响的分子途径。 通过微阵列进行的表达谱分析将用于评估母体和胎儿组织中的差异基因表达（特定目的1），以及在胎盘功能背景下表征的相关信号传导途径（特定目的2）。 单独地，基于标记连锁分析的全基因组扫描将使我们能够鉴定和定位显性修饰基因座（特异性目的3），其在最严重影响的同基因129，Hsf 1敲除小鼠中赋予胎盘性状增加的存活（特异性目的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信息，以计划旨在特定细胞中转基因表达HSF 1和创建同类菌株的拯救策略（具体目标4）。 我们的工作将为HSF 1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，这些信息可以构成一个合理的基础，干预涉及HSF 1在诊断，预后和治疗条件，如先兆子痫和胎儿宫内生长迟缓在人类。

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.