comment in budget justification. ? As requested, we added io the limitations of Aim 2 an explanation that our mouse experiments are designed to model global hypoxia, akin to that seen with maternal hypoxia (e.g., asthma, R to L shunt, high altitude). Such injury pathways are shared with pre-placental maternal vascular remodeling abnormalities, but not with post-placental fetal hypoxia conditions. A reviewer also asked how the application addresses the "outcome of hypoxia" and the functional implications of hypoxia. Throughout the application we emphasized the role of hypoxia in disrupting trophoblast lipid metabolism and causing lipotoxicity. Hypoxia experiments are included in every aim of the amended proposal, including the modified Aim 3. ? As requested, in Aim 2 we added to a description of the results anticipated from the control experiment where we deploy food restriction without hypoxia. ? We thank the reviewers for suggesting the inclusion of HIF1 a in our mechanistic assays in Aim 3. We expanded these experiments to define the cross-talk between PPARy and HIFIa in this context. These experiments buttress the role of Aim 3 in resolving key mechanisms in trophoblastic LD and lipid trafficking. ? A reviewer asked if Project III overiaps with the Pi's current R01 grant (ES011597). This is definitely not the case. The currently funded grant (ES011597) focuses on physiological functions of PPARy, the regulation and function of FATPs, and the role of PUFAs in trophoblast toxicity. PHS 398 (Rev. 6/09) Page 134

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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