HSF 1 Requirements in Extraembryonic Development

胚胎外发育中的 HSF 1 要求

• 批准号: 6918087
• 负责人: Ivor James Benjamin
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-13 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918087
• 关键词: India; behavioral /social science research tag; clinical research; contraceptives; disease /disorder proneness /risk; family structure /dynamics; female; human subject; infant mortality; interpersonal relations; marriage /marital status; role; social status; socioeconomics; spouse abuse; violence; women' s health

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.

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会，以表征靶向基因突变在重要生物学过程或特定途径中的生理作用，这既不是怀疑的，也不是预测的。这项建议的广泛和长期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扮演的生理角色，并确定涉及HSF1的调控网络可以被操纵以促进子宫内存活和生长的策略。HSF1/-基因敲除小鼠表现出复杂的表型，包括胎盘缺陷、存活减少但取决于遗传背景的变量，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(S)似乎与其作为应激条件下热休克蛋白基因的主要应激诱导反式激活因子的特征无关。有待检验的主要假设是，调控热休克因子1(HSF1)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相互作用的信号通路来控制海绵状滋养层的增殖、分化或维持。两种独立和公正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(特定目标1)，以及相关的信号通路将在胎盘功能的背景下表征(特定目标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显性修饰基因座(特定目标3)，该基因座可在对等基因129，HSF1基因敲除小鼠影响最严重的情况下提高胎盘性状的存活率(特定目标4)。这些创新方法的主要优点是，两个发现平台将产生互补的信息，以计划旨在特定细胞中转基因表达HSF1的救援策略和创造同源菌株(特定目标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，这些信息可以构成对人类先兆子痫和宫内发育迟缓等疾病的诊断、预后和治疗中涉及HSF1的干预的合理基础。