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

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.

Grant Number: 1R03HD113870-01
NIH Institute/Center: NIH
Principal Investigator: Amy Abell