Multi-omics of the Iron Homeostasis Pathway in Patient Outcomes Following aSAH

项目摘要/摘要：动脉瘤性蛛网膜下腔出血(ASAH)是一种重要的 每年影响近30,000美国人的健康问题，并导致长期的功能障碍。 占所有中风相关死亡的25%，ASAH是一种毁灭性的伤害，留下了令人震惊的66% 幸存者的生活质量降低，大约50%的人仍然完全依赖照顾者。它是 人们普遍认为，ASAH后的不良功能结局在很大程度上是由于 急性恢复期继发并发症包括迟发性脑缺血(DCI)。 不幸的是，DCI的病因在很大程度上仍不清楚，开发治疗干预措施的研究正在进行中 由于无法识别DCI的高危患者而受到阻碍。临床前模型阐明了代谢 导致一种独特类型的细胞死亡的机制，这种死亡依赖于细胞内的铁和 导致ASAH后动物继发性缺血性脑损伤(类似于DCI)。这些研究还包括 证明铁络合剂能有效减少与这一并发症相关的神经细胞死亡。 尽管有这些证据，铁稳态并不被认为是ASAH后的一个重要的临床途径，因为 缺乏对人类的研究。根据我们的研究和文献中的证据，我们提出 ASAH后患者预后的实质性差异主要集中在遗传/表观遗传差异上 铁稳态途径；我们的总体目标是更好地了解这些生物 机械装置。拟议研究的具体目的是：1)描述 铁稳态和变异性相关候选基因脑脊液DNA甲基化的变化 对ASAH患者的急性和长期预后的影响以及2)检测基因多态之间的关系 与铁稳态和急性和长期结局的可变性相关的候选基因 阿萨。使用与广泛的患者结局表型数据相关联的生物检验剂，这些数据收集自一家大型、 正在进行的纵向研究，建议的研究将使用多元Logistic回归建模，轨迹 用于探索表观遗传学和遗传学的建模、候选基因关联和基因-基因交互分析 铁稳态途径的变异性。拟议的研究符合NINR的使命，因为它 专注于通过破译遗传对症状变异性的影响来改善个人的健康 和患者的结果，并具体解决了许多症状科学的创新问题，包括 在NINR战略计划中，包括阐明与机制和评估有关的OMIC指标 症状和机制路径可以区分潜在的症状群轨迹。这 新的研究将为一系列研究奠定基础，以确定临床相关的生物标志物和证据- 以ASAH患者为基础的治疗，以改善患者的预后，也是 申请人的研究计划。

PROJECT SUMMARY/ABSTRACT: Aneurysmal subarachnoid hemorrhage (aSAH) is a significant public health problem affecting nearly 30,000 Americans annually and causing long-term functional impairments. Accounting for 25% of all stroke-related deaths, aSAH is a devastating injury that leaves an astounding 66% of survivors with a reduced quality of life and approximately 50% remaining fully dependent on caregivers. It is widely accepted that the poor functional outcomes following aSAH are due in large part to the development of secondary complications during the acute recovery phase including delayed cerebral ischemia (DCI). Unfortunately, the causes of DCI remain largely unknown and studies to develop therapeutic interventions are hindered by the inability to identify patients at high risk for DCI. Preclinical models have elucidated metabolic mechanisms that contribute to a unique type of cell death which is dependent upon intracellular iron and results in secondary ischemic brain injury (similar to DCI) in animals following aSAH. These studies also demonstrate that iron chelators effectively reduce neuronal cell death associated with this complication. Despite this evidence, iron homeostasis is not recognized as an important clinical pathway post-aSAH due to a dearth of research in humans. Based on evidence from our studies as well as the literature, we propose that the substantial variability in patient outcomes following aSAH largely centers on genetic/epigenetic variation in the iron homeostasis pathway; our overall goal is to gain a better understanding of these biological mechanisms. The specific aims of the proposed research are: 1) to characterize the relationship between changes in cerebrospinal fluid DNA methylation of candidate genes related to iron homeostasis and variability of acute and long-term outcomes following aSAH and 2) to examine the relationship between polymorphisms in candidate genes related to iron homeostasis and variability of acute and long-term outcomes following aSAH. Using biospecimens linked to extensive patient outcome phenotype data collected from a large, ongoing longitudinal study, the proposed research will use multiple logistic regression modeling, trajectory modeling, candidate gene association, and gene-gene interaction analyses to explore epigenetic and genetic variability of iron homeostasis pathway. The proposed study is in line with the mission of NINR in that it focuses on improving the health of individuals by deciphering the genetic influence on variability in symptoms and patient outcomes and specifically addresses many of the symptom science innovative questions included in the NINR strategic plan including elucidating the omic indicators related to the mechanisms and assessment of symptoms and the mechanistic pathways that can distinguish underlying symptom cluster trajectories. This novel study will lay the foundation for a line of research to identify clinically relevant biomarkers and evidence- based therapies for aSAH victims in order to improve patient outcomes and also represents a beginning step in the applicant's program of research.