Epigenomics of Patient Outcomes after Aneurysmal SAH

描述（由申请方提供）：本申请侧重于了解蛛网膜下腔出血（aSAH）后的病理生理学。许多研究强调了aSAH幸存者所忍受的并发症;然而，缺乏研究来解决潜在的、潜在的可改变的病理生理学，以及导致aSAH幸存者死亡的破坏。 aSAH后并发症的发生率和严重程度，严重阻碍了适当干预措施的发展。DNA甲基化是成人脑中基因表达和功能调节的关键机制，并且似乎在脑缺血事件期间的神经保护中起重要作用。迟发性脑缺血（DCI）发生在aSAH后的急性期，是后来发生并发症的主要原因;然而，DCI的病理生理学和并发症的发生尚不清楚。我们假设表征代表aSAH后CNS环境的甲基化组将阐明与DCI和患者结局相关的病理生理学。该项目的目的是使用科学、高通量、基于基因组的方法，关注aSAH后前14天代表CNS的DNA中发生的每日全基因组甲基化组变化;确定该甲基化组数据是否影响DCI以及aSAH后并发症的发展;使用全基因组数据来确定在aSAH后14天内经历甲基化变化并影响DCI和并发症的基因和途径;使用ChIP-Seq方法进一步研究由全基因组甲基化组数据提名的位点;并且通过使用aSAH幸存者的独立队列，数据将经历复制测试以及预测价值的评估。该项目汇集了一个真正的多学科研究团队，其中包括人类遗传学家，统计遗传学家，神经创伤临床专家以及aSAH后急性症状和慢性并发症的临床专家。本项目的最终目标和总体影响是了解aSAH后发生的动态过程，以获得信息，这些信息在未来将导致开发aSAH后可以提供的干预措施，以减少DCI的发生，改善aSAH后的CNS环境，并最终减少aSAH幸存者的并发症负担。

DESCRIPTION (provided by applicant): This application focuses on understanding the pathophysiology following aneurysmal subarachnoid hemorrhage (aSAH). Many studies highlight the complications that aSAH survivors endure; however there is a dearth of research that address the underlying, potentially alterable pathophysiology, and disruption that lead to the occurrence and severity of post aSAH complications, severely hindering the development of appropriate interventions. DNA methylation is a key mechanism for regulation of gene expression and function in the adult brain and appears to play an important role in neuroprotection during ischemic events in the brain. Delayed cerebral ischemia (DCI), occurring during the acute phase following aSAH, is a major contributor to the complications that later develop; however the pathophysiology of DCI and the development of complications is not known. We hypothesize that characterizing the methylome representing the CNS environment post aSAH will clarify the pathophysiology associated with DCI and patient outcomes. The aims of this project focus on the daily genome-wide methylomic changes that occur in DNA representing the CNS for the first 14 days after aSAH using state of the science, high-throughput, genomic based methodologies; determining if this methylomic data impacts DCI as well as the development of complications after aSAH; using the genome-wide data to determine genes and pathways that experience methylomic changes over the 14 days after aSAH and have an impact DCI and complications; further investigate sites nominated by the genome-wide methylomic data using a ChIP-Seq approach; and through the use of an independent cohort of aSAH survivors the data will undergo a replication test as well as assessment for predictive value. This project brings together a truly multidisciplinary research team, which includes human geneticists, statistical geneticists, clinical experts in neurotrauma, and clinical experts in acute symptoms and chronic complications after aSAH. The ultimate goal and the overall impact of this project is to provide an understanding of the dynamic processes that occur after aSAH to obtain information that, in the future, will lead to the development of interventions that can be delivered after aSAH to reduce the occurrence of DCI, improve the CNS environment post aSAH, and ultimately reduce the burden of complications in the aSAH survivor.