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Common Fund Data Supplement to A Multivariate Predictive Model for Long- term Disability Post Subarachnoid Hemorrhage in Caucasian and African Populations (NIH/NINR 1R01NR017407)

白种人和非洲人群蛛网膜下腔出血后长期残疾的多变量预测模型的共同基金数据补充 (NIH/NINR 1R01NR017407)

基本信息

批准号：
9983373
负责人：
Ansley Stanfill
金额：
$ 6.17万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-08 至 2021-07-31
项目状态：
已结题

项目摘要

This application is being submitted in response to NOT-RM-19-009, as a supplement to NIH/NINR 1R01NR017407 (PI: Stanfill). Aneurysmal subarachnoid hemorrhage (aSAH) strikes relatively young individuals and carries high rates of mortality and severe disability. While social, clinical, and genetic factors have each independently been shown to be associated with disability, there remains a large portion of unexplained variability as well as great disparities in outcome for African American patients as compared to Caucasian patients. The objective of the parent R01 proposal is to lay the foundation for effective intervention by accurately identifying individuals most at risk and identifying the factors contributing to the racial disparities seen for these populations. Guided by our strong pilot data and leveraging the power of two existing databases, we have two specific aims: 1) Using social, clinical, and genetic data, we propose to develop a predictive model for disability 12 months post aSAH in a Caucasian cohort; and 2) Using social, clinical, and genetic data, we propose to develop a predictive model for disability 12 months post aSAH in an African American cohort. The uniformity of the two models will be compared for insights into factors driving the disparities in outcome between these groups. As a part of the parent project, we expect to find genomic variants in our candidate dopaminergic and serotonergic pathways that are influential for prediction of disability outcomes. However, the parent R01 does not have the ability to collect gene expression data, so it is not clear how these variants alter transcription and thus neurotransmitter activity for pharmacologic intervention. This supplemental proposal will fill that gap through the use of Common Fund Genotype-Tissue Expression (GTEx) data. This dataset allows the measurement of our selected SNPs for gene expression in brain tissue, which will give an opportunity to explore how the brain environment is altered in a patient with these genetic variants. Furthermore, the GTEx project also allows us the ability to determine whether similar changes occur in blood, and which in turn could be used as surrogate markers for brain expression. This information could form the crux of a point of care test, by which personalized pharmacologic intervention might occur. We propose three supplemental specific aims: 1) Using GTEx genotype and expression data from brain tissue samples, test the association between SNPs and gene expression for identified SNPs in our candidate dopaminergic and serotonergic pathways; 2) Using GTEx genotype and expression data from blood samples, test the association between SNPs and gene expression for identified SNPs in our candidate dopaminergic and serotonergic pathways; and 3) Use GTEx data to test the association of gene expression data between brain and whole blood tissues. The proposed work will leverage the data collected from the GTEx project to expand the funded R01 study to gene expression in whole blood and brain tissue(s). This will have significant impact by informing precisely targeted interventions to improve outcomes and quality of life post aSAH.

本申请是针对 NOT-RM-19-009 提交的，作为 NIH/NINR 的补充 1R01NR017407（PI：斯坦菲尔）。动脉瘤性蛛网膜下腔出血 (aSAH) 发病相对较年轻个人的死亡率和严重残疾率很高。虽然社会、临床和遗传因素虽然每一项都被独立地证明与残疾有关，但仍有很大一部分与非裔美国患者相比，无法解释的变异性以及结果的巨大差异白种人患者。母版 R01 提案的目标是为有效干预奠定基础通过准确识别风险最大的个人并确定造成种族差异的因素对于这些人群来说。以我们强大的试点数据为指导，并利用两个现有的力量数据库，我们有两个具体目标：1）利用社会、临床和遗传数据，我们建议开发一个白种人队列中 aSAH 后 12 个月的残疾预测模型； 2) 利用社会、临床和遗传数据，我们建议开发一个非洲人 aSAH 后 12 个月残疾的预测模型美国队列。将比较两个模型的一致性，以深入了解驱动因素这些群体之间的结果差异。作为父项目的一部分，我们期望找到基因组我们的候选多巴胺能和血清素能通路的变异对残疾预测有影响结果。但亲本R01不具备收集基因表达数据的能力，因此尚不清楚这些变异如何改变转录，从而改变神经递质活性以进行药物干预。这补充提案将通过使用共同基金基因型组织表达（GTEx）来填补这一空白数据。该数据集允许测量我们选择的脑组织基因表达的 SNP，这将提供了一个机会来探索具有这些遗传变异的患者的大脑环境如何改变。此外，GTEx项目还使我们能够确定血液中是否发生类似的变化，反过来又可以用作大脑表达的替代标记。这些信息可以形成护理点测试的关键，通过该测试可能会发生个性化的药物干预。我们提出三个补充具体目标：1) 使用来自脑组织样本的 GTEx 基因型和表达数据，测试 SNP 与我们的候选多巴胺能和基因表达中已识别的 SNP 之间的关联血清素能途径； 2) 使用来自血液样本的 GTEx 基因型和表达数据，测试关联性在我们的候选多巴胺能和血清素能中识别出的 SNP 之间的 SNP 和基因表达之间的关系途径； 3）使用GTEx数据测试大脑和整体之间基因表达数据的关联性血液组织。拟议的工作将利用从 GTEx 项目收集的数据来扩大资助范围 R01 研究全血和脑组织中的基因表达。这将通过通知产生重大影响精确针对性的干预措施，以改善 aSAH 后的结果和生活质量。