Abstract

Neonatal hypoxia ischemia (HI) is an injury caused to the immature brain due to reduced cerebral blood flow which is associated with life-long neurological impairments. HI causes oxidative protein folding in the endoplasmic reticulum (ER), which results in ER stress. Generation of reactive oxygen species (ROS), from cytochrome P450 members (CYP) and NADPH-P450 reductases (NPR), in combination with activation of the unfolded protein response (UPR) are two major consequences of ER stress that cause oxidative damage and cell death. Herein we identified the role of Bax Inhibitor-1 (BI-1), an evolutionary conserved protein encoded by the Transmembrane Bax inhibitor Motif Containing 6 (TMBIM6) gene, in protection from ER stress after HI injury in the neonatal rat. As BI-1 has multimodal properties that can target a wide array of pathophysiological consequences after injury, our main objective was to evaluate BI-1’s protective mechanisms by overexpressing it, using viral-mediated gene delivery of human adenoviral-TMBIM6 (Ad-TMBIM6) vector, in an in vitro and in vivo model of HI. Following the Rice-Vannuci model, ten-day old (P10) rat pups underwent rightunilateral carotid artery ligation followed by 1.5h of hypoxia. Our results showed that overexpression of BI-1 ameliorated short and long-term deficits following HI. There was

a significant reduction in percent infarcted area which was linked with attenuation of apoptosis, reduction of ROS accumulation and inhibition of pro-inflammatory mediators. BI-1 mediated protection was observed to be via both inhibition of IRE1α signaling, a stress sensor protein part of the UPR response, and P4502E1 activity, a major contributor of ROS generation. Attenuation of apoptosis was associated with a decrease in IRE1α- XBP1 levels while decreased levels of P4502E1 coupled with upregulation of Nrf-2 and HO-1, anti-oxidant enzymes, were correlated with a reduction in ROS generation and inflammation. In conclusion we established that overexpression of BI-1 attenuated the morphological and neurological consequences post HI via inhibition of ER stress induced pathways. This new finding may help to provide a basis for BI-1 as a potential therapeutic target.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Zhang, John H.

Second Advisor

Angeles, Danilyn

Third Advisor

Brantely, Eileen

Fourth Advisor

Tang, Jiping

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2018

Date (Title Page)

6-2018

Language

English

Library of Congress/MESH Subject Headings

Gene Therapy; Hypoxia-Ischemia; Brain; Fetal Hypoxia; Infant; Newborn; Fetal Brain

Subject - Local

Neonatal Hypoxia-Ischemia; Cerebral Blood Flow; Neurological Impairment

Type

Dissertation

Page Count

164

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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