Perinatal hypoxic-ischemic brain injury (HI) is one of the leading causes of neurologic morbidity in the pediatric population with sequelae such as cerebral palsy, intellectual disability, and epilepsy. Despite the known plasticity of the immature brain, we still have very little in the way of therapies to actively ameliorate the potentially devastating consequences of this disease. Neurogenesis is one aspect of plasticity with the potential to improve outcomes after such injury. Neural stem and progenitor cells (NSPs) reside in discrete regions of the brain postnatally, and while we know that they can alter behavior in response to numerous stimuli, we still do not have a strong enough understanding of the fundamental mechanisms by which these cells respond to injury. The experiments described in this career development plan have been designed to use advanced strategies in clonal analysis to better understand the heterogeneity of the response of subventricular zone (SVZ) NSPs to perinatal HI. With this knowledge, I propose also to define a role for the epigenetic mechanism of active DNA demethylation as an early trigger for perinatal HI-induced neurogenesis. Finally I aim to investigate changes in the methylation patterns of Notch and BDNF, genes known to play important roles in NSP regulation, to link active DNA demethylation with known players in the phenomenon of neurogenesis. In the process we will also be using the emerging strategy of single cell RNA sequencing to describe transcriptome shifts that occur following perinatal HI and identify novel pathways of interest in regulating the response of NSPs to this type of injury. In conjunction with the other career development activities described in this proposal, this plan will prepare me for an independent research career further exploring neurogenesis after perinatal HI and translating this knowledge into strategies to better understand and hopefully intervene during the acute recovery period following brain injury to improve our management of such patients.
Perinatal hypoxic-ischemic brain injury has devastating consequences, impairing quality of life for patients and their families and carrying with it substantial costs to society. The proposed studies investigating the mechanisms by which neural stem and progenitor cells respond to such injury will provide a better understanding of the role of neurogenesis in the acute recovery phase and hopefully lead to novel therapeutic targets for improving outcomes.