In the United States, fetal alcohol spectrum disorders (FASD) represent the leading preventable cause of birth defects and neurodevelopmental delay with life-long implications. FASD affects an estimated 40,000 infants in the US each year, with 2-5% of younger school-age children having FASD. Currently, prediction of FASD during pregnancy is not available, and there are no readily available cures against FASD. It is widely believed that early detection of FASD and its subsequent intervention strategies are critical to allow earliest and most effective therapeutic interventions. While fetal alcohol exposure targets multiple organs and systems, the brain constitutes the most severely affected organ, exhibiting both structural and functional abnormalities. As neuronal development critically depends on the oxygen delivery, nutritional supply and waste removal by cerebral circulation, recent studies have been paying increasing attention to the fetal cerebral circulation as a critical target of maternal alcohol consumption. However, the timing and mechanisms that govern fetal cerebrovascular response to alcohol remain elusive. One of the major obstacles that preclude rapid advancement of the studies on fetal cerebral circulation is lack of high-resolution imaging technique that would be suitable for imaging of small lab animal species. Current proposal is put forth by the collaborating teams of bioengineers and cerebrovascular physiologists with the overall goal of delivering a high-speed 3D photoacoustic tomography (PAT) that will allow non-invasive, simultaneous visualization of all the embryos in a mouse utero and track their development into adulthood longitudinally to study the association between alcohol exposure-induced changes in fetal hemodynamics and cerebrovascular outcome after birth. Another obstacle to developing effective treatments to alleviate symptoms and develop preventive measures against FASD is a relatively limited knowledge on relevant targets for alcohol, including targets within fetal cerebral arteries. In this regard, current proposal will focus on cerebral artery mitochondria. Critical role of mitochondria in regulating cerebral artery function is well documented, and there is no doubt that mitochondrial is one of the major sensors for alcohol as shown in liver and neurons. In our recent pioneered work we documented persistent up-regulation of fetal cerebral artery proteome in response to alcohol exposure during mid- pregnancy. However, systematic studies on cerebral artery mitochondria alterations in response to prenatal alcohol exposure remain to be performed and the role of alcohol targeting of fetal cerebral artery mitochondria remains to be established. To overcome these obstacles in the field, we propose to complete three related Aims: (1) We will optimize a high-speed PAT system for 3D high-resolution brain imaging of rodents; (2) We will develop advanced software for improved PAT 3D image reconstruction and analysis; (3) We will trace cerebrovascular morphological and functional changes following fetal alcohol exposure into adulthood, with the focus on fetal cerebral vessel density, artery diameter and mitochondrial function.
The goal of this research is to develop a novel photoacoustic imaging approach that will allow non- invasive, simultaneous three-dimensional visualization of all the embryos in a mouse utero and track their birth/adulthood longitudinally to study the association between maternal alcohol exposure induced fetal hemodynamic changes and the outcome of fetal alcohol spectrum disorder (FASD) after birth. The functional focus of this proposal is on fetal cerebral artery mitochondria. Our work will provide better understanding of the pathophysiology of FASD and offer new therapeutic target(s) against this condition.
