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.
| Su, Kuo-Hui; Cao, Junyue; Tang, Zijian et al. (2016) HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat Cell Biol 18:527-39 |
| Taylor, Ryan P; Benjamin, Ivor J (2005) Small heat shock proteins: a new classification scheme in mammals. J Mol Cell Cardiol 38:433-44 |
