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

aSAH 后患者预后中铁稳态途径的多组学研究

基本信息

批准号：
9390141
负责人：
Lacey W. Heinsberg
金额：
$ 4.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9390141
关键词：
Accounting Acute Address Affect Age of Onset American Aneurysmal Subarachnoid Hemorrhages Animals Biological Biological Markers Blood Vessels Brain Injuries Candidate Disease Gene Caregiver Burden Caregivers Caring Cell Death Cerebral Ischemia Cerebrospinal Fluid Cessation of life Clinical Pathways Complication DNA Methylation Data Development Discipline of Nursing Early Intervention Education Emotional Epigenetic Process Expenditure Family Foundations Funding Genes Genetic Genetic Polymorphism Genotype Glasgow Outcome Scale Goals Health Healthcare Homeostasis Human Individual Injury Intervention Iron Iron Chelating Agents Ischemic Brain Injury Knowledge Life Link Literature Logistic Regressions Longitudinal Studies Mediator of activation protein Mentors Metabolic Mission Modeling Monitor Nurses Outcome Pathology Pathway interactions Patient-Focused Outcomes Patients Phase Phenotype Population Pre-Clinical Model Public Health Quality of life Recovery Recruitment Activity Research Resources Risk Sampling Science Secondary to Signs and Symptoms Strategic Planning Stroke Survivors Symptoms Therapeutic Therapeutic Intervention Time Work base cell type clinically relevant cohort epigenetic variation evidence base experience functional disability functional outcomes gene interaction genome-wide high risk human subject improved innovation mortality neuron loss novel parent project phenotypic data pre-clinical preclinical study predictive marker programs psychologic response symptom cluster symptom science therapeutic target therapy development

项目摘要

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.

项目摘要/摘要：动脉瘤性蛛网膜下腔出血 (aSAH) 是一个重要的公众疾病健康问题每年影响近 30,000 名美国人并导致长期功能障碍。 aSAH 占所有中风相关死亡的 25%，是一种毁灭性的损伤，导致 66% 的人死亡幸存者的生活质量下降，大约 50% 的人仍然完全依赖护理人员。这是人们普遍认为，aSAH 后功能不良的结果在很大程度上是由于急性恢复期的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然未知，开发治疗干预措施的研究仍在进行中。由于无法识别 DCI 高危患者而受到阻碍。临床前模型已阐明代谢导致独特类型细胞死亡的机制依赖于细胞内铁和导致 aSAH 后动物继发性缺血性脑损伤（类似于 DCI）。这些研究还证明铁螯合剂可以有效减少与这种并发症相关的神经元细胞死亡。尽管有这些证据，但铁稳态并未被认为是 aSAH 后的重要临床途径，因为缺乏对人类的研究。根据我们的研究和文献的证据，我们建议 aSAH 后患者预后的显着差异主要集中在遗传/表观遗传变异上铁稳态途径；我们的总体目标是更好地了解这些生物机制。拟议研究的具体目标是：1）表征之间的关系与铁稳态和变异相关的候选基因脑脊液 DNA 甲基化的变化 aSAH 后的急性和长期结局以及 2) 检查多态性之间的关系与铁稳态以及急性和长期结果变异相关的候选基因萨哈。使用与从大量患者收集的大量患者结果表型数据相关的生物样本正在进行的纵向研究，拟议的研究将使用多重逻辑回归模型，轨迹建模、候选基因关联和基因-基因相互作用分析，以探索表观遗传和遗传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的影响来改善个体的健康和患者的结果，并特别解决了许多症状科学创新问题，包括 NINR 战略计划中包括阐明与机制和评估相关的组学指标症状和可以区分潜在症状群轨迹的机制路径。这新颖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- 为 aSAH 受害者提供基于治疗的方法，以改善患者的治疗结果，这也代表了申请人的研究计划。