Development of an animal model to test HDAC6 as a drug target to reduce and/or prevent fetal growth restriction

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PROJECT SUMMARY Disruption of fetal growth results in severe consequences to human health, including increased fetal and neonatal morbidity and mortality, as well as potential lifelong health problems. Fetal growth restriction (FGR) occurs in up to 10% of all human pregnancies. Unfortunately, treatments for FGR are lacking. Molecular mechanisms promoting fetal growth represent potential therapeutic strategies to treat and/or prevent FGR. We have identified a previously unknown role for the mitogen activated protein kinase kinase kinase 4 (MAP3K4) in promoting fetal and placental growth by inducing the expression and activity of the insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (IR). In recent work published in 2022, we discovered that inactivation of MAP3K4 kinase activity by a mutation in the kinase domain results in FGR. MAP3K4 Kinase-Inactive (KI) mice display high lethality prior to weaning and persistent growth reduction of surviving adults. Expression and activation of the IGF1R and IR are reduced in both cultured KI trophoblasts and KI placentas. Mechanism(s) by which MAP3K4 controls these receptors represent novel approaches to treat FGR. MAP3K4 inhibits the expression and activity of histone deacetylase 6 (HDAC6). KI trophoblasts have elevated HDAC6 expression and activity, and reduction of HDAC6 restores IGF1R and IR expression and activity. Based on these findings, we hypothesize that HDAC6 may also be hyperactive in KI placentas, and HDAC6 inhibition may rescue and prevent FGR. The availability of highly selective and well-tolerated HDAC6 inhibitors provides a unique opportunity for developing a therapy to treat FGR. However, it remains unknown if targeting HDAC6 during pregnancy will improve fetal and placental growth. Our preliminary data show that inhibition of HDAC6 during pregnancy increased the survival of KI embryos during development. However, this rescue may be due in part to off target effects of HDAC6 inhibitors. To test our prediction that deletion of HDAC6 will prevent FGR in KI mice, we propose to genetically delete HDAC6 from MAP3K4 KI mice by mating them with HDAC6 knockout mice. Survival and growth of MAP3K4 KI mice lacking HDAC6 will be assessed. In addition, fetal and placental size will be measured, and placental expression and activity of the IGF1R, IR, and Akt will be quantified. These new results will be compared to growth restriction and lethality observed in the presence of elevated HDAC6. We predict that deletion of HDAC6 from MAP3K4 KI individuals will improve fetal growth and increase survival, indicating that HDAC6 inhibitors may represent a new therapeutic tool to treat FGR.