[R01] Synergistic Effect of Nicotine and Antiretrovirals on Placental Development
Ente: National Institute on Drug Abuse
Scadenza: 2030-05-31
Importo max: 711.164 EUR
Paese: US
Descrizione
Project Summary
Background: The number of women living with human immunodeficiency virus type 1 (HIV-1) getting pregnant
while on antiretroviral therapy is steadily rising. This is due to the growing availability of antiretroviral drugs
(ARVs) at affordable access worldwide. Each year, more than a million women LWH have given birth while on
ART. Although ART has significantly reduced the rate of vertical HIV-1 transmission to less than 1%, risks of
adverse events on fetal outcomes linked to in utero ARVs exposure remain a major concern. Studies showed
that HIV-1-exposed uninfected (HEU) children are at increased risk for preterm delivery, infectious morbidity,
mortality, immune abnormalities, and impaired growth or neurodevelopment; yet there are gaps in understanding
of how in utero ARVs exposures may impact placental development, the key regulator of fetal growth. One of
the major reasons behind this limitation include co-morbidities complicating the interpretations. There is a
substantial knowledge gap about the effects of comorbid ARV’s and substance use on placenta. Several
addictive agents are commonly used by pregnant woman LWH, however, globally nicotine exposure through
smoking or tobacco use remains as one of the major co-morbidities. Smoking is an independent risk factor for
adverse fetal outcomes, such as preterm delivery, low birth weight, and intrauterine growth restriction. However,
whether and how, ARVs and nicotine together produce synergistic effect to exacerbate adverse effects on
placental development affecting pregnancy outcomes is unknown. Objective: Uncover how co-exposure of
nicotine exacerbate ARVs-linked adverse effects on placenta development and employ long-acting (LA) delivery
means to alleviate the impact of co-morbidity by attenuating ARVs-linked adverse effects. For ARVs, the focus
will be on commonly prescribed and first-line integrase strand transfer inhibitors (INSTIs). Preliminary data: We
observed that dolutegravir (DTG) reduced MMP-2 activity and HIF-1α protein accumulation under both normoxic
and hypoxic conditions in cultured trophoblasts, reducing migration abilities. Moreover, nicotine further
exacerbated the effect of DTG on HIF-1α protein accumulation. DTG-induced abnormalities in these proteins
influenced impairment in placenta vasculature development in rodent model. Hypothesis: Synergistic effects of
INSTI and nicotine on MMPs and HIF-1α impairs placental morphology and vasculature development. Research
Strategy: (1) Assessment of effects of co-exposure of INSTIs and nicotine on trophoblasts functions and
associated alterations in global proteomic profile; (2) Determine synergistic impact on placental development in
a rodent model; and (3) Evaluate injectable long-acting delivery means for protective outcomes. Expectations:
Nicotine exacerbates adverse impact of INSTIs on placenta development and that long-acting delivery approach
will attenuate the impact of co-morbidity by attenuating INSTIs’ expos
Istituzione: UNIVERSITY OF NEBRASKA MEDICAL CENTER
PI: Aditya N Bade
Progetto: 5R01DA064132-02
Settori: National Institute on Drug Abuse
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