Exosomal Gasdermin D Mediated Lung to Brain Crosstalk in Preterm Brain Injury

摘要

ABSTRACT I sincerely thank NIH for the opportunity to apply for this Administrative Supplement for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards Facing Critical Life Events (NOT-OD-23-032). My research is currently supported by an R01 grant from NHLBI (1RO1HL156803-01A1), which I obtained in August 2020. The major goal of this grant is to determine the mechanisms by which circulating extracellular vesicles (EVs) mediate lung-to-brain crosstalk and their contribution to brain injury and neurodevelopmental impairment (NDI) in preterm infants. EVs play a crucial role in inter-organ communications. Pyroptosis is a newly described form of inflammatory cell death that is solely regulated by gasdermin D (GSDMD), an inflammasome-activated membrane “pore-forming” protein. Activation of GSDMD depends on the activation of caspase-1, which is achieved by assembling an inflammasome complex with the apoptosis-associated speck-like protein containing a card (ASC). Our studies demonstrated that preterm infants who develop bronchopulmonary dysplasia (BPD), a chronic lung disease, have increased expression of ASC and GSDMD in their circulating EVs at 1 week of age. Importantly, the adoptive transfer of these EVs into the circulation of normal newborn mice induced lung inflammation and impaired brain development. These findings led us to propose a novel model that links BPD, EV-ASC, EV-GSDMD, and brain injury. The central hypothesis of this model is that ASC-containing and GSDMD-containing EVs are released from the lung into the circulation during the evolving stage of BPD, and brain neuronal uptake of these EVs results in neural cell pyroptosis and NDI. We proposed three Specific Aims in the parent grant to test this hypothesis. In this Administrative Supplement, we will concentrate our research efforts on Specific Aim 1 to further characterize the sources of EV-ASC and EV-GSDMD, whether they are derived from alveolar epithelial cells (AEC) or alveolar macrophages (AM). In Specific Aim 2, we will develop new methods to isolate AEC-derived EVs and AM-derived EVs and determine their effects on brain injury and NDI by adoptive transfer experiments in newborn mice.