The Role of HIF-1 alpha in Vasculotrophic Influence of Neural Stem Cells

HIF-1 α 在神经干细胞血管营养影响中的作用

基本信息

批准号：
8015248
负责人：
Tamara Roitbak
金额：
$ 22.16万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-19 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8015248
关键词：
Address Adult Area Behavior Blood Vessels Brain Brain Injuries Brain Ischemia Caliber Cell Nucleus Cell Survival Cerebral Ischemia Dextrans Embryo Endothelial Cells Exhibits Gene Deletion Genes Genetic Transcription Glucose Goals HIF1A gene Hypoxia Hypoxia Inducible Factor In Vitro Injection of therapeutic agent Injury Ischemia Ischemic Brain Injury Knock-out Knockout Mice Lead Link Mediating Middle Cerebral Artery Occlusion Morphogenesis Mus Neurons Oxygen Pathway interactions Permeability Play Population Process Property Publishing Reperfusion Therapy Role Signal Pathway Signal Transduction Source Stem cells Stroke Stroke prevention System Tamoxifen Testing Therapeutic Uses Transplantation Vascular Endothelial Growth Factors Vascular remodeling angiogenesis brain remodeling brain tissue density deprivation design dextran immunocytochemistry improved in vivo migration mouse model nerve stem cell nestin protein neuronal replacement public health relevance relating to nervous system repaired research study response stem stem cell niche stroke recovery transcription factor vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Neural stem/progenitor cells (NSPCs) have been proposed as an endogenous cellular source for the neuronal replacement and treatment of stroke. However, there is little evidence of a causal link between the formation of new neurons and symptomatic recovery from stroke, suggesting that the neurogenic response to stroke may be important in repair processes apart from replacement of lost neurons. We had demonstrated that NSPCs exhibit a strong ability to support endothelial cell survival, morphogenesis and angiogenesis following ischemia. These findings lead to our central hypothesis that neural stem cells provide protection for brain endothelial cells leading to the functional remodeling of brain vasculature following ischemia. NSPCs reside within a specialized stem cell niche, in close proximity to blood vessels, suggesting a functional interaction between neural progenitors and endothelial cells, which may be critical in revascularization and repair following stroke. In our preliminary studies, the vasculotrophic effect of NSPCs was mediated via vascular endothelial growth factor VEGF and governed by hypoxia-inducible factor HIF-1a, both constitutively expressed in NSPCs in vitro and in vivo. The goal of the proposed study is to further explore the role of HIF-1a in vasculotrophic properties of NSPCs, using a conditional HIF-1a knockout mouse model. We will test whether NSPC-specific HIF-1a gene deletion will result in impaired revascularization in response to in vitro and in vivo ischemia. The second goal is to determine whether NSPC stimulate post-ischemic revascularization and thus, improve brain tissue reperfusion following hypoxia. Dynamic changes in vasculogenesis following experimental focal ischemia will be assessed in wild type and HIF-1a conditional knockout adult mice using histological analyses, immunocytochemistry and in vivo fluorescent dextran injections. The overarching hypothesis of our proposal is that the vasculotrophic effects of NSPCs are governed by transcription factor HIF-11, both under normal conditions and following hypoxia. To address this hypothesis, the following Specific Aims are proposed: Specific Aim 1: To determine the role of HIF-1a in NSPC-mediated support of endothelial cells under conditions of in vitro ischemia. Specific Aim 2: To determine the effects of NSPC-specific HIF-1a gene deletion on stroke-induced angiogenesis in vivo. The results of the proposed project will expose a functional link between neurogenic and angiogenic responses to cerebral ischemia, which may have important implications for the therapeutic use of stem cells to support revascularization following stroke injury. PUBLIC HEALTH RELEVANCE: Our main hypothesis is that neural stem cells protect brain blood vessels and induce new vessel formation following stroke. The goal of our study is to identify the molecules and mechanisms responsible for the neural stem cell-induced protection. Our findings may have important implications for the therapeutic use of stem cells in the treatment and prevention of stroke.

描述（由申请人提供）：神经干/祖细胞（NSPC）已被提议作为神经元替代和中风治疗的内源细胞来源。然而，几乎没有证据表明新神经元的形成与中风症状恢复之间存在因果关系，这表明除了替换丢失的神经元之外，对中风的神经源性反应可能在修复过程中也很重要。我们已经证明 NSPC 在缺血后表现出强大的支持内皮细胞存活、形态发生和血管生成的能力。这些发现引出了我们的中心假设，即神经干细胞为脑内皮细胞提供保护，导致缺血后脑血管系统的功能重塑。 NSPC 存在于一个专门的干细胞生态位中，靠近血管，这表明神经祖细胞和内皮细胞之间存在功能性相互作用，这对于中风后的血运重建和修复可能至关重要。在我们的初步研究中，NSPCs 的血管营养作用是通过血管内皮生长因子 VEGF 介导的，并受缺氧诱导因子 HIF-1a 控制，两者在体外和体内均在 NSPCs 中组成型表达。本研究的目的是利用条件性 HIF-1a 敲除小鼠模型，进一步探讨 HIF-1a 在 NSPC 血管营养特性中的作用。我们将测试 NSPC 特异性 HIF-1a 基因缺失是否会导致响应体外和体内缺血的血运重建受损。第二个目标是确定 NSPC 是否刺激缺血后血运重建，从而改善缺氧后的脑组织再灌注。将使用组织学分析、免疫细胞化学和体内荧光葡聚糖注射在野生型和 HIF-1a 条件敲除成年小鼠中评估实验性局灶性缺血后血管生成的动态变化。我们提议的总体假设是，无论是在正常条件下还是在缺氧后，NSPC 的血管营养作用均受转录因子 HIF-11 的控制。为了解决这一假设，提出以下具体目标：具体目标 1：确定 HIF-1a 在体外缺血条件下 NSPC 介导的内皮细胞支持中的作用。具体目标 2：确定 NSPC 特异性 HIF-1a 基因缺失对中风诱导的体内血管生成的影响。该项目的结果将揭示神经源性和血管生成性脑缺血反应之间的功能联系，这可能对干细胞支持中风损伤后血运重建的治疗用途具有重要意义。公共健康相关性：我们的主要假设是神经干细胞可以保护脑血管并在中风后诱导新血管形成。我们研究的目的是确定负责神经干细胞诱导保护的分子和机制。我们的研究结果可能对干细胞在中风的治疗和预防中的应用具有重要意义。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Roles for HIF-1α in neural stem cell function and the regenerative response to stroke.

HIF-1α 在神经干细胞功能和中风再生反应中的作用。

DOI：
发表时间：
2012-02-14
期刊：
影响因子：
2.7
作者：
Cunningham, Lee Anna;Candelario, Kate;Li, Lu
通讯作者：
Li, Lu

In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke.

体内抑制 miR-155 可促进实验性小鼠中风后的恢复。

DOI：
发表时间：
2015-09-09
期刊：
影响因子：
0
作者：
Caballero;Pena;Lordkipanidze, Tamar;Bragin, Denis;Yang, Yirong;Erhardt, Erik Barry;Roitbak, Tamara
通讯作者：
Roitbak, Tamara