Germinal matrix hemorrhage (GMH) is a major problem of premature infants because a large number of these babies develop cerebral palsy, hydrocephalus and mental retardation. Components of the blood brain barrier, which potentially contribute to the stabilization of cerebral vessels, include endothelial tight junctions, astrocyte end-feet and capillary pericytes. Since pericytes provide structural integrity to blood vessels and since our preliminary data suggest that tight junction molecules and coverage of astrocyte end-feet are developed in premature infants vulnerable to GMH, we hypothesize that 1) pericytes are decreased in germinal matrix vasculature compared to cerebral cortex and white matter and that 2) the expression of growth factors recruiting pericytes during angiogenesis including angiopoetins, platelet derived growth factor-B (PDGF-B) and transforming growth factor-beta (TGF-beta) and their receptors are decreased in germinal matrix compared to the other areas of the brain. Since prenatal glucocorticoids decrease the incidence of GMH as well as modulate the expression of these growth factors in blood vessels of organs other than the brain, we also propose that glucocorticoid treatment increases the recruitment of pericytes in germinal matrix by modulating the expression of growth factors angiopoietin, PDGF-B and TGF-beta and their receptors. We will determine the expression of angiopoietin, PDGF-B, TGF-beta and their respective receptors Tie-1, -2, PDGFR-beta, ALK-1 and -5 in the germinal matrix compared to cortex and white matter of the frontal lobe in human fetuses and premature infants (16-40 weeks) using immunohistochemistry and in-situ hybridization. In addition we will quantify pericytes using electron microscopy. We will assess the effect of glucocorticoids on pericytes and the growth factors recruiting pericytes as well as their respective receptors in preterm infants exposed and not exposed to prenatal glucocorticoids. We will also examine the effect of glucocorticoids in a neonatal rabbit model to eliminate confounding variables present in premature infants. Our data may help in understanding the etiology of GMH and may explain the basis of prenatal glucocorticoid therapy. It may also identify new strategies in the prevention and treatment of GMH. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS050586-01A1
Application #
6986974
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Golanov, Eugene V
Project Start
2005-05-24
Project End
2007-04-30
Budget Start
2005-05-24
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$214,896
Indirect Cost
Name
New York Medical College
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Ballabh, Praveen (2010) Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 67:1-8
Zia, Muhammad T; Csiszar, Anna; Labinskyy, Nazar et al. (2009) Oxidative-nitrosative stress in a rabbit pup model of germinal matrix hemorrhage: role of NAD(P)H oxidase. Stroke 40:2191-8
Chua, Caroline O; Chahboune, Halima; Braun, Alex et al. (2009) Consequences of intraventricular hemorrhage in a rabbit pup model. Stroke 40:3369-77
Ballabh, Praveen; Xu, Hongmin; Hu, Furong et al. (2007) Angiogenic inhibition reduces germinal matrix hemorrhage. Nat Med 13:477-85