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: 7140544
• 负责人: PRAVEEN BALLABH
• 金额: $ 17.61万
• 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 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140544
• 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（由申请人提供）：老年性基质出血（GMH）是早产儿的主要问题，因为这些婴儿中有大量发生脑瘫、脑积水和智力迟钝。血脑屏障的成分可能有助于脑血管的稳定，包括内皮紧密连接、星形胶质细胞末端足和毛细血管周细胞。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，紧密连接分子和星形胶质细胞末端足的覆盖在易受GMH影响的早产儿中发展，我们假设：1）与大脑皮层和白色物质相比，周细胞在生发基质脉管系统中减少，并且2）在血管生成期间招募周细胞的生长因子的表达，包括血管生成素，与脑的其它区域相比，血小板衍生生长因子-B（PDGF-B）和转化生长因子-β（TGF-β）及其受体在脑胚基质中减少。由于产前糖皮质激素降低GMH的发病率，以及调节这些生长因子的表达，在血管中的器官，而不是大脑，我们还建议，糖皮质激素治疗增加招聘周细胞在germinal矩阵通过调节生长因子血管生成素，PDGF-B和TGF-β及其受体的表达。我们将使用免疫组织化学和原位杂交技术，测定人胎儿和早产儿（16-40周）大脑皮层和额叶的白色物质中血管生成素、PDGF-B、TGF-β及其各自受体Tie-1、-2、PDGFR-β、ALK-1和-5在大脑皮层基质中的表达。此外，我们将使用电子显微镜定量周细胞。我们将评估糖皮质激素对周细胞和生长因子招募周细胞及其各自的受体在早产儿暴露和不暴露于产前糖皮质激素的影响。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。它还可以确定新的策略，在预防和治疗GMH。

项目成果

Consequences of intraventricular hemorrhage in a rabbit pup model.

• DOI: 10.1161/strokeaha.109.549212
• 发表时间: 2009-10
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Chua CO;Chahboune H;Braun A;Dummula K;Chua CE;Yu J;Ungvari Z;Sherbany AA;Hyder F;Ballabh P
• 通讯作者: Ballabh P