Among the physiological abnormalities reported in fetal alcohol spectrum disorder (FASD), both clinical studies and studies using animal models and have demonstrated marked impairments in immune competence, including delayed and deficient development of the immune system, depressed or overactive immune responses to challenge, and increased risk for infection and various forms of cancer, with many changes persisting into adolescence and adulthood. Impaired immune function in the alcohol-consuming mother, altered immunity at the fetal-placental interface, and disruption of the finely-tuned bidirectional communication between the neuroendocrine and neuroimmune systems appear to play a role in the deficits observed in prenatal alcohol-exposed (PAE) offspring. The present proposal investigates when and how PAE can impact immune function, and will elucidate possible mechanisms underlying PAE's adverse effects on the mother, the fetus, and the interaction between maternal and fetal systems. The role of early life experience in programming the set-point or tone for stress and immune responsiveness to later life challenge will also be investigated.
Our Specific Aims are: 1) To investigate the effects of alcohol consumption on neuroimmune function of the pregnant dam and fetus, and their possible link, in mediating alcohol-induced immune impairments in dams and PAE offspring via cytokine analysis (Expt 1A) and fetal microglia responsivity (Expt 1B). 2) To elucidate a developmental neuroimmune profile of PAE compared to control offspring from birth to adulthood to gain insight into how PAE, in the presence or absence of stress during the adolescent period, may differentially alter resting neuroimmune function and set the stage for vulnerability to stress or immune challenge in later life;3) To investigate the role of early life immune challenge, imposed on an already sensitized organism (PAE), in modulating differential immune and neural outcomes of PAE and control animals following immune challenge in adulthood;4) To elucidate mechanisms underlying the differential course of inflammation in PAE and control offspring observed previously, and to investigate possible differential effects of stress during adolescence, a sensitive developmental period, in modulating the course of inflammation in adulthood. Our working hypothesis is that fetal programming of stress and immune systems by PAE results in a primed, vulnerable pro-inflammatory-biased organism that is predisposed to increased responsiveness to immune challenge in adulthood. Elucidation of mechanisms underlying neuroimmune deficits in PAE offspring is critical for understanding the nature of the immune abnormalities seen in children with FASD, which will improve clinical care of these children, and ultimately improve their long-term health and well-being.
Among the physiological abnormalities reported in fetal alcohol spectrum disorder (FASD) are deficits in immune competence. The present proposal investigates when and how PAE can impact immune function, and will elucidate possible mechanisms underlying alcohol's adverse effects on the mother, the fetus, and the interaction between maternal and fetal systems. Elucidation of mechanisms underlying neuroimmune deficits in PAE offspring is critical for understanding the nature of the immune abnormalities seen in children with FASD, which will improve clinical care of these children, and ultimately improve their long-term health and well-being.
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