Role for MicroRNAs in Ischemic Tolerance

MicroRNA 在缺血耐受中的作用

• 批准号: 8046406
• 负责人: JULIE Anne SAUGSTAD
• 金额: $ 28.8万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046406
• 关键词: Attenuated; Behavioral Assay; Binding; Biochemical; Bioinformatics; Brain; Cell Death; Cessation of life; Clinical; Development; Dissociation; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Gene Expression; Genes; Genetic Transcription; Genetic Translation; Genome; Genomics; Goals; Heart Arrest; Histology; Human; Injury; Ischemia; Ischemic Brain Injury; Ischemic Preconditioning; Knockout Mice; Label; Laboratory Study; Link; Mass Spectrum Analysis; Measures; Messenger RNA; Methyl-CpG-Binding Protein 2; MicroRNAs; Microarray Analysis; Mission; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Nuclear; Nuclear Protein; Nuclear Proteins; Phosphorylation; Prevention; Protein Biosynthesis; Protein Dephosphorylation; Proteins; Proteome; Proteomics; Public Health; Publishing; RNA Binding; RNA-Induced Silencing Complex; Regulation; Research; Role; Run-On Assays; Stimulus; Stroke; Testing; Time; Transcript; Transcription Repressor/Corepressor; Transient Ischemic Attack; Translating; Translations; United States National Institutes of Health; adeno-associated viral vector; disability; improved; in vivo; neuroprotection; novel; novel strategies; overexpression; preconditioning; protein expression; public health relevance; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Ischemic preconditioning, induced by a sub-lethal duration of ischemia, triggers endogenous responses that protect the brain against a subsequent, severe ischemic insult, a phenomenon known as "tolerance". Ischemic tolerance requires new protein synthesis, involves genomic reorganization, and is transient. Our long-term objective is to elucidate the molecular mechanisms by which the preconditioning stimulus induces tolerance. Our studies support the conceptual framework that preconditioning regulates the interaction between mRNAs and RISCs leading to increased translation of the mRNAs, particularly those that function as transcriptional regulators that can reprogram the genome and attenuate responses to ischemic injury, resulting in tolerance. We will the following aims to test specific mechanisms of ischemic preconditioning-induced tolerance, including (1) the molecular mechanisms of ischemic preconditioning-induced regulation of RISCs, (2) the regulation of RISC-bound RNAs by ischemic preconditioning, (3) the regulation of the nuclear proteome and transcription rates by ischemic preconditioning, and (4) to overall test of the conceptual framework: tolerance by regulation of miRNAs and mRNAs. These studies are directly related to the mission of NIH and NINDS in that ischemic brain injuries are among the most common and important causes of disability and death worldwide. Clinical evidence suggests that endogenous preconditioning triggered by a transient ischemic attack is present in the human brain. While not without challenges, promising strategies to elicit endogenous brain protection are under clinical development. Thus, we will use a combination of biochemical, molecular, and proteomic studies to examine these distinct and novel mechanisms of in vivo ischemic preconditioning on the induction of tolerance. Our goal is to provide evidence for miRNAs as effectors of endogenous neuroprotection that will translate into novel strategies for the treatment or prevention of ischemic brain injury. PUBLIC HEALTH RELEVANCE: Ischemic brain injuries due to stroke or cardiac arrest are common and prominent causes of disability and death worldwide. Yet, there is evidence to suggest that a transient ischemic attack can actually protect the human brain from a subsequent, more severe ischemic attack. As we can model this protection in laboratory studies, this research will improve public health through the identification of novel mechanisms that contribute to this protection, and their translation into clinical strategies for the treatment or prevention of ischemic brain injury.

描述(由申请人提供)：由亚致死时间的缺血诱导的缺血预适应，触发内源性反应，保护大脑免受随后严重的缺血性损伤，这种现象被称为“耐受”。缺血耐受需要新的蛋白质合成，涉及基因组重组，而且是短暂的。我们的长期目标是阐明预适应刺激诱导耐受的分子机制。我们的研究支持这样的概念框架，即预适应调节mRNAs和RISCs之间的相互作用，导致mRNAs的翻译增加，特别是那些发挥转录调节功能的mRNAs，可以对基因组进行重新编程，减弱对缺血损伤的反应，从而产生耐受。我们将从以下几个方面探讨缺血预适应诱导耐受的具体机制，包括(1)缺血预适应诱导RISCs调控的分子机制，(2)缺血预适应对RISC结合的RNAs的调控，(3)缺血预适应对核蛋白质组和转录速率的调节，以及(4)对概念框架的全面检验：通过调节miRNAs和mRNAs来实现耐受。这些研究与NIH和NINDS的使命直接相关，因为缺血性脑损伤是全球最常见和最重要的残疾和死亡原因之一。临床证据表明，短暂性脑缺血发作引发的内源性预适应存在于人脑中。虽然并非没有挑战，但诱导内源性脑保护的有希望的策略正在临床开发中。因此，我们将结合生化、分子和蛋白质组学研究来研究体内缺血预适应诱导耐受的这些独特而新颖的机制。我们的目标是为miRNAs作为内源性神经保护的效应器提供证据，这将转化为治疗或预防缺血性脑损伤的新策略。 公共卫生相关性：中风或心脏骤停造成的缺血性脑损伤是全世界常见和突出的残疾和死亡原因。然而，有证据表明，短暂性脑缺血发作实际上可以保护人类大脑免受随后更严重的脑缺血发作的影响。由于我们可以在实验室研究中模拟这种保护，这项研究将通过识别有助于这种保护的新机制来改善公共健康，并将其转化为治疗或预防缺血性脑损伤的临床策略。