Role for MicroRNAs in Ischemic Tolerance

描述（由申请人提供）：由亚致死持续时间的缺血引起的缺血预适应会触发内源性反应，保护大脑免受随后的严重缺血性损伤，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，并且是暂时的。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：预处理调节 mRNA 和 RISC 之间的相互作用，从而增加 mRNA 的翻译，特别是那些作为转录调节因子发挥作用的转录调节因子，可以重新编程基因组并减弱对缺血性损伤的反应，从而产生耐受性。我们接下来的目标是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RISCs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）总体测试概念框架：通过miRNA和mRNA调节耐受。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世界最常见和最重要的致残和死亡原因之一。临床证据表明，人脑中存在由短暂性脑缺血发作引发的内源性预处理。虽然并非没有挑战，但引发内源性大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检查体内缺血预处理对耐受诱导的这些独特且新颖的机制。我们的目标是为 miRNA 作为内源性神经保护效应物提供证据，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：中风或心脏骤停引起的缺血性脑损伤是全世界残疾和死亡的常见且主要原因。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识别有助于这种保护的新机制并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.