Project name: PPARg activation enhances myelination and neurological recovery in premature rabbits with intraventricular hemorrhage

Description: We hypothesized that activation of PPARg would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPARg expression in microglia of both preterm human infants and rabbit kits. The treatment with PPARg agonist or PPARg overexpression by adenovirus delivery further elevated PPARg levels in microglia, reduced pro-inflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPARg-induced novel genes for purinergic signaling, cAMP generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-seq analyses of microglia revealed PPARg-triggered downregulation of several pro-inflammatory genes and transcripts having roles in Parkinson’s disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPARg activation enhanced myelination and neurological function in kits with IVH.Overall design: We performed two sets of RNA-seq: a) To address the effect of PPARg overexpression on microglial transcriptome, we performed a RNA-seq analysis on CD45Low/CD11b+ microglia isolated from the cerebral hemispheres of Ad-PPARg or Ad-GFP treated kits with IVH by FACS at D7; b) To determine the effect of PPARg overexpression on OPC transcriptome, we performed a RNA-seq analysis on O4+ OPC isolated from the cerebral hemispheres of Ad-PPARg and Ad-GFP treated preterm kits with IVH at D7.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2021-08-24