Interdisciplinary Initiatives Program Round 12 - 2024
Project Investigators:
Shirit Einav, Medicine - Infectious Diseases and Microbiology & Immunology
Anca Pasca, Pediatrics - Neonatal and Developmental Medicine
Jon Bernstein, Pediatrics - Medical Genetics
Carla Shatz, Biology and Neurobiology
Purvesh Khatri, Medicine - Biomedical Informatics - Research Institute for Immunity, Transplantation and Infection
Abstract:
The unmet need: Pregnancy-related infections account for approximately 50% of neurodevelopmental disorders, yet the underlying mechanisms remain unclear. Thus, there are no existing biomarkers and therapeutics to predict or prevent most of these devastating conditions. Our goal is to decipher how the fetal brain responds to infections, in order to advance the development of prognostic tools for early identification of fetuses at risk and strategies to prevent neurodevelopmental defects. This project will focus on congenital Zika syndrome (CZS) as a disease model and expand to other infections and non-infectious conditions posing a growing global maternal and fetal threat.
We hypothesize that alterations in neuronal and brain immune cell responses to Zika infection and cell-cell communications mediate the observed fetal defects and are driven by genetic and/or epigenetic factors. We also hypothesize that some features of these responses overlap across infectious and non-infectious environmental triggers. To test these hypotheses, we will further 3D brain organoid models to analyze unique samples derived from a Brazilian cohort of twins discordant for CZS. We will profile the epigenomic and transcriptomic responses at a single cell level in distinct cell populations derived from CZS and nonaffected twins via innovative technologies developed and/or utilized by the Einav and Khatri labs. Neuronal functions will be mechanistically probed using technologies established at the Pasca lab. Technologies established at the Bernstein lab for identifying the genetic basis for rare congenital neurodevelopmental disorders will also be used. Lastly, we will identify unique and overlapping hallmarks of neurodevelopmental defects across infections and other triggers as attractive candidate biomarkers and/or targets for interventions.
This interdisciplinary work is designed to unravel fundamental mechanisms underlying neurodevelopmental disorders while advancing novel broadly-applicable technologies for neurodevelopment and neurodegeneration studies. Discovering predictive biomarkers and/or targets for prevention may transform the current paradigm for managing these disorders, thereby improving maternal and fetal health.
