Role for MicroRNAs in Ischemic Tolerance

描述（由申请人提供）：缺血预处理，由亚致死持续时间的缺血诱导，触发内源性反应，保护大脑免受随后的严重缺血损伤，这种现象称为“耐受”。缺血耐受需要新的蛋白质合成，涉及基因组重组，并且是短暂的。我们的长期目标是阐明预处理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，即预处理调节mRNA和RISC之间的相互作用，导致mRNA的翻译增加，特别是那些作为转录调节因子发挥作用的mRNA，这些转录调节因子可以重新编程基因组并减弱对缺血性损伤的反应，从而导致耐受。我们将通过以下目的来测试缺血预处理诱导耐受的具体机制，包括（1）缺血预处理诱导的RISC调节的分子机制，（2）缺血预处理对RISC结合RNA的调节，（3）缺血预处理对核蛋白质组和转录速率的调节，以及（4）对概念框架的总体测试：通过调节miRNAs和mRNAs的耐受性。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残疾和死亡的最常见和最重要的原因之一。临床证据表明，由短暂性脑缺血发作触发的内源性预处理存在于人脑中。虽然并非没有挑战，但引发内源性脑保护的有希望的策略正在临床开发中。因此，我们将结合生物化学、分子生物学和蛋白质组学研究来探讨这些独特的和新的机制，在体内缺血预处理诱导耐受。我们的目标是为miRNAs作为内源性神经保护的效应物提供证据，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：由于中风或心脏骤停引起的缺血性脑损伤是全球范围内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。由于我们可以在实验室研究中模拟这种保护，因此这项研究将通过鉴定有助于这种保护的新机制以及将其转化为治疗或预防缺血性脑损伤的临床策略来改善公众健康。

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.