Investigating the impact of chromosome 21 dosage on the placenta secretome and neurodevelopment

PROJECT SUMMARY This research proposal aims to investigate the critical role of the placenta-brain axis in Down Syndrome (DS) development. DS or Trisomy 21 (T21) results from trisomy or partial translocation of human chromosome 21 (HSA21), impacting roughly 1 in 700 births. Both placental and brain alterations are well established in DS, yet underlying mechanisms and prenatal treatments for these abnormalities are lacking. A key unanswered question is whether placental abnormalities contribute to altered cortical development in individuals affected by DS. Here, I investigate the effects of HSA21 dosage and HSA21-linked genes APP and SOD1 on placental function, alterations in neuroactive compounds secreted from placental syncytiotrophoblast (STBs) and the resulting neurodevelopmental consequences. I hypothesize that increased dosage of HSA21, driven by HSA21-linked genes APP and SOD1, causes impaired STB formation and secretion of crucial neuroendocrine factors, which subsequently contributes to cell non- autonomous neurodevelopmental perturbations. I will test my hypothesis with two aims. First, I will determine perturbation in T21 STB function and secretome and test the involvement of SOD1, APP and oxidative stress. Second, I will investigate the contribution of an impaired STB secretome to neurodevelopmental perturbations in T21. Hypothesis testing will be done by using a novel model of the human placenta-brain axis using human induced pluripotent stem cell (hiPSC)-derived STBs and cerebral organoids. The research outcomes are expected to address a key unanswered question in the field: do placental abnormalities contribute to altered cortical development in humans affected by DS? Our approach will uncover the role of specific T21 genes on T21-induced oxidative stress on the placenta-brain axis in neurodevelopment, test dietary compounds that could improve T21 dysfunction and more broadly facilitate our understanding of the role of placental signals in fetal brain development. Our proposed research will contribute to identifying potential therapeutic targets for prenatal treatment and enable real-time assessment of T21. Furthermore, our innovative hiPSC based placenta-brain axis will be instrumental in comprehending how high-risk pregnancies, substance misuse, and environmental chemical exposure impact fetal brain development. I will be trained for a scientific career during this proposal by my mentor Dr. Erwin, co-mentor Dr. Mueller, collaborators Dr. Burd, Dr. Rasmussen and Dr. Paquola, and lab members Dr. Sawada, Dr. Wang, and Ms. McCord.