Pericytes in Pathogenesis of Germinal-Matrix Hemorrhage

周细胞在生殖基质出血发病机制中的作用

• 批准号: 6986974
• 负责人: PRAVEEN BALLABH
• 金额: $ 21.49万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-24 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986974
• 关键词: angiopoietins; blood brain barrier; cerebral hemorrhage; chemoprevention; electron microscopy; frontal lobe /cortex; gene expression; glucocorticoids; growth factor receptors; human tissue; immunocytochemistry; in situ hybridization; laboratory rabbit; macrophage; platelet derived growth factor; postmortem; premature infant human; receptor expression; transforming growth factors; vascular smooth muscle; white matter

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：生发基质出血（GMH）是早产儿的一个主要问题，因为大量早产儿出现脑瘫、脑积水和智力低下。血脑屏障的组成部分可能有助于脑血管的稳定，包括内皮紧密连接、星形胶质细胞端脚和毛细血管周细胞。由于周细胞为血管提供结构完整性，并且由于我们的初步数据表明，在易受 GMH 影响的早产儿中形成了紧密连接分子和星形胶质细胞端足的覆盖，因此我们假设 1) 与大脑皮层相比，生发基质脉管系统中的周细胞减少2) 在血管生成过程中募集周细胞的生长因子的表达，包括血管生成素、血小板衍生生长因子-B (PDGF-B) 和转化生长与大脑其他区域相比，生发基质中的β因子（TGF-β）及其受体减少。由于产前糖皮质激素可降低 GMH 的发生率并调节除大脑以外的器官血管中这些生长因子的表达，因此我们还建议糖皮质激素治疗通过调节生长因子血管生成素的表达来增加生发基质中周细胞的募集、PDGF-B 和 TGF-β 及其受体。我们将确定生发基质中血管生成素、PDGF-B、TGF-β 及其各自受体 Tie-1、-2、PDGFR-β、ALK-1 和 -5 与额叶皮质和白质的表达情况使用免疫组织化学和原位杂交在人类胎儿和早产儿（16-40 周）中进行检测。此外，我们将使用电子显微镜量化周细胞。我们将评估糖皮质激素对暴露和未暴露于产前糖皮质激素的早产儿的周细胞和招募周细胞的生长因子及其各自受体的影响。我们还将检查糖皮质激素在新生兔模型中的作用，以消除早产儿中存在的混杂变量。我们的数据可能有助于了解 GMH 的病因，并可能解释产前糖皮质激素治疗的基础。它还可能确定预防和治疗 GMH 的新策略。