Abstract

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Approximately 60 % of preterm babies and 2% of full term infants suffer from asphyxia. Asphyxia related death accounts for approximately 23% of neonatal mortality annually. Many therapeutic interventions show promise in the laboratory but fail in clinics. A thorough understanding of mechanisms by which promising therapeutic intervention confers its neuroprotection is necessary to promote smoother transitions from bench to the bedside. Erythropoietin (EPO), a hematopoietic growth factor that increases oxygen availability during hypoxia/ischemia is associated with cell survival and neuroprotection in: in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. Thus the central aim of this proposal is: to determine the key mediators of EPO-induced neuroprotection and the mechanisms by which this occurs in: in vitro and in vivo models of hypoxia ischemia. Two alternate pathways of EPO-induced neuroprotection were elucidated in vitro using oxygen and glucose deprivation to mimic hypoxia ischemia. Our findings showed that EPO treatment resulted in an upregulation of tissues inhibitor of matrix metalloproteinase (TIMP)-1 and inhibition of hypoxia inducible factor (HIF-1α) both of which subsequently decreased in matrix metalloproteinase (MMP)-9 and promoted neuroprotection. MMP-9 inhibition was associated with neuroprotection in both pathways thus, inferring that inhibition of MMP-9 is one of the primary mechanisms of EPO-induced neuroprotection. We also observed that EPO-induced neuroprotection was reversed by inhibition of TIMP-1 or prolyl hydroxylase (PHD)-2. This lends to the conclusion that TIMP-1 and PHD-2 are the key mediators of EPO-induced neuroprotection in: in vivo and in vitro models of hypoxia ischemia.

LLU Discipline

Microbiology and Molecular Genetics

Department

Basic Sciences

School

School of Medicine

First Advisor

Tang, Jiping

Second Advisor

Fletcher, Hansel

Third Advisor

Sowers, Lawrence C.

Fourth Advisor

Zhang, John H.

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2011

Date (Title Page)

12-1-2011

Language

English

Library of Congress/MESH Subject Headings

Hypoxia ischemia;

Subject - Local

Neuro-protection; Neonatal mortality; Hypoxic ischemic brain injury (HIBI); Erythropoietin (EPO)

Type

Dissertation

Page Count

111 p.

Digital Format

Application/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 & Dissertations

Collection Website

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

Repository

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

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