[F32] B Cells in Preeclampsia: Long-term Effects on Offspring
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2028-04-10
Importo max: 76.780 EUR
Paese: US
Descrizione
Preeclampsia (PE), new-onset hypertension during pregnancy with multi-organ dysfunction, is associated with
chronic immune activation and is the leading cause of morbidity and mortality for the mother and fetus. Delivery
of the baby is the current treatment for PE. Today’s therapies focus on managing symptoms instead of preventing
the occurrence. Preterm delivery of the fetus is a primary cause of fetal growth restriction (FGR) and this is
associated with an elevated risk for cardiovascular, metabolic, and neurological disorders later in life. In fact, PE
is associated with autism spectral disorder in offspring and early signs of cognitive disorders in the mother. PE
women exhibit increased activated T helper cells and B cells producing agonistic autoantibodies to the
angiotensin II type 1 receptor (AT1-AA) which have been implicated in oxidative stress, increased sensitivity to
angiotensin II, and cerebrovascular dysfunction in the mother. Our lab has demonstrated that AT1-AA can be
blocked with a novel inhibitory peptide ‘n7AAc’ that reduces blood pressure and cerebrovascular dysfunction in
PE rat models. While ‘n7AAc’ has not been tested clinically, we have demonstrated its efficacy and safety in
several preclinical models of PE and PE offspring. We hypothesize that AT1-AA produced by B cells stimulated
in PE pregnancies contribute both to the PE syndrome during pregnancy as well as postpartum risk for
neurovascular disease in previously PE women and their children. We will address this hypothesis by isolating
B cells from the placentas of PE patients and adoptively transferring them into pregnant nude athymic rats and
then examine blood pressure, immune cells, cerebrovascular function, and cognitive function. Additionally, we
will allow a second group of animals to deliver and examine birth weight and growth in the offspring, as well as
blood pressure, immune cells, cerebrovascular function, and cognitive function in the adult offspring and
postpartum dams. Finally, we will treat the B cell recipients with the inhibitory peptide ‘n7AAc’ and measure the
same outcomes during pregnancy as well as in the adult offspring and postpartum dams. Based on our
preliminary findings we hypothesize that AT1-AA blockade will improve maternal outcomes in B cell recipients
and reduce postpartum risks following PE in both the dams and offspring. The following specific aims will be
used to test this hypothesis.
Specific Aim 1: To test the hypothesis that CD20+ B cells from PE women are stimulated to produce AT1-AA
and cause hypertension as well as cerebrovascular and cognitive dysfunction during pregnancy and in 12-week
postpartum dams as well as male and female offspring.
Specific Aim 2: To test the hypothesis that perinatal or postnatal blockade of AT1-AA in recipient dams of PE
CD20+ B cells will improve hypertension as well as cerebrovascular and cognitive dysfunction during pregnancy
and in postpartum dams and offspring.
Istituzione: UNIVERSITY OF MISSISSIPPI MED CTR
PI: Nathan E. Campbell
Progetto: 5F32HD118681-02
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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