In vivo Inhibition of Specific microRNAs to Support Post-Stroke Revascularization

体内抑制特定 microRNA 以支持中风后血运重建

基本信息

批准号：
8912551
负责人：
Tamara Roitbak
金额：
$ 33.05万
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：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912551
关键词：
Animals Area Belief Blood Vessels Blood capillaries Brain Brain Injuries Cell Death Cell Proliferation Cell physiology Cerebral Ischemia Cerebrovascular Circulation Cessation of life Clinical Complex Data Development Distal Endothelial Cells Gene Expression Genes Goals Health Hypoxia Immunofluorescence Immunologic In Vitro Infarction Injection of therapeutic agent Injury Investigation Ischemia Ischemic Brain Injury Knowledge Laser Scanning Microscopy Lead Magnetic Resonance Imaging Messenger RNA Methods MicroRNAs Microarray Analysis Middle Cerebral Artery Occlusion Mission Morphogenesis Mus Natural regeneration Nerve Degeneration Neurons Outcome Post-Transcriptional Regulation Process Public Health Publishing Recovery Recovery of Function Regulation Research Role Signal Pathway Signal Transduction Signaling Molecule Staining method Stains Stroke Techniques Testing Therapeutic Therapeutic Intervention Time Tissues United States National Institutes of Health Up-Regulation Vascular blood supply Vascular remodeling Vascularization Venous angiogenesis base brain tissue burden of illness capillary disability human disease improved in vitro Assay in vivo inhibitor/antagonist innovation migration neuroinflammation novel strategies novel therapeutics overexpression post stroke restoration stroke recovery stroke therapy two-photon

项目摘要

DESCRIPTION (provided by applicant): Stroke is a major public health problem and is a leading cause of serious, long-term disability in the US and worldwide. Significant scientific effort is focused on the strategies to enhance angiogenesis after cerebral ischemia, which may improve clinical outcomes during post-stroke recovery. Endothelial morphogenesis is an essential component of vascular remodeling, involving complex interactions between genes and signaling molecules. microRNAs (miRNAs), short mRNA-interfering molecules, control post-transcriptional gene expression in many tissues, including vasculature. miRNA dysregulation has been recently associated with numerous human diseases; therefore, modulation of miRNA expression may offer a significant therapeutic potential. Our objective and long-term goal is to employ regulation of vascular miRNA expression as a therapeutic method for stroke treatment. The central hypothesis is that in vivo inhibition of specific miRNAs will support revascularization and thus, brain recovery following stroke. This hypothesis is based on our published and preliminary studies suggesting that three specific miRNAs, miR-155, miR-100 and miR-let-7i, could coordinate a revascularization process. The rationale for the proposed research is that once we determine the role of miR-155, miR-100 and miR-let-7i in post-stroke angiogenesis, we can support this process through modulation of miRNA activity in vivo. To test the central hypothesis, we propose the following Aims: 1) To study the effect of specific miRNAs on the in vitro endothelial proliferation, invasion, migration and overall capillary-forming ability. 2) To study the influence of the in vivo inhibition of specific miRNAs on post-stroke revascularization. 3) To assess whether pro-angiogenic effect of specific miRNA inhibition correlates with the improved recovery after stroke. We believe that the proposed research is innovative because it offers a new approach to post-stroke recovery: the direct regulation of post-ischemic angiogenesis through modulation of specific miRNA expression. We believe that the proposed research is significant because it is expected to lead to the development of novel therapeutic strategies for improving the post-ischemic recovery.

描述（由申请人提供）：中风是一个主要的公共卫生问题，也是美国和全世界严重、长期残疾的主要原因。大量的科学努力集中在增强脑缺血后血管生成的策略上，这可能会改善中风后恢复期间的临床结果。内皮形态发生是血管重塑的重要组成部分，涉及基因和信号分子之间复杂的相互作用。 microRNA (miRNA) 是一种短 mRNA 干扰分子，控制许多组织（包括脉管系统）中的转录后基因表达。最近，miRNA 失调与多种人类疾病相关。因此，调节 miRNA 表达可能具有显着的治疗潜力。我们的客观和长期目标是利用血管 miRNA 表达的调节作为中风治疗的治疗方法。中心假设是体内抑制特定 miRNA 将支持血运重建，从而支持中风后的大脑恢复。这一假设基于我们已发表的初步研究，表明三种特定的 miRNA（miR-155、miR-100 和 miR-let-7i）可以协调血运重建过程。这项研究的基本原理是，一旦我们确定了 miR-155、miR-100 和 miR-let-7i 在中风后血管生成中的作用，我们就可以通过调节体内 miRNA 活性来支持这一过程。为了检验中心假设，我们提出以下目标：1）研究特定miRNA对体外内皮增殖、侵袭、迁移和总体毛细血管形成能力的影响。 2) 研究特定miRNA的体内抑制对卒中后血运重建的影响。 3) 评估特定 miRNA 抑制的促血管生成作用是否与中风后恢复的改善相关。我们相信所提出的研究具有创新性，因为它为中风后恢复提供了一种新方法：通过调节特定 miRNA 表达来直接调节缺血后血管生成。我们相信，所提出的研究意义重大，因为它有望导致开发改善缺血后恢复的新治疗策略。