Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Zeljka Korade, Ph.D, D.V.M.

Second Advisor

Karoly Mirnics, M.D., Ph.D.

MeSH Headings

Brain ischemia, hypoxia, infant, newborn, micrornas

Abstract

Neonatal hypoxic-ischemic brain injury (HIBI) is a devastating injury resulting from impaired blood flow and oxygen delivery to the brain at or around the time of birth. The subsequent metabolic failure and cellular injury in the brain can be partially attenuated by rapid initiation of therapeutic hypothermia, but even with prompt induction of hypothermia, more than one in four survivors suffer from major developmental disabilities – an indication of the critical need for more effective therapies. MicroRNAs (miRNA) may be able to act as therapeutic targets in neonatal HIBI; however, very little is known about the endogenous expression of miRNAs after neonatal HIBI nor the role that extracellular vesicle (EV)-delivered miRNAs may play in the neuroprotective effects of EV administration. Using temporal and regional sampling of brain tissue in a mouse model of neonatal HIBI followed by next-generation miRNA sequencing (miRNA-Seq), miRNA profiles of the different brain regions at 30 minutes and the whole brain at 24 and 72 hours after injury were obtained. EVs were then modified to optimize neuroprotection by hypoxia preconditioning, administered intranasally to the mouse model, and the EV miRNA content was analyzed by miRNA-Seq. The studies identified several promising miRNAs for future investigations into miRNA-based therapeutic interventions. Given the multifactorial nature of neonatal HIBI, it is likely that a combination of miRNAs would need to be targeted to achieve maximal benefit. Because of this, the list of promising miRNAs was grouped by targeted pathways, and future investigations should consider assessing the effects of altering one or more miRNA from each of the miRNA clusters. Additional mechanistic studies will be necessary to demonstrate whether the differentially expressed miRNAs may be beneficial or pathologic and whether the miRNAs detected in the EVs play a significant role in the neuroprotection seen after hypoxia preconditioned EV administration. Ultimately, given their broad effect profile, ease of administration, and small size allowing for effective blood-brain barrier crossing, miRNAs represent promising targets for improving brain injury and reducing developmental impairments in neonates suffering from HIBI.

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