Genomic and Transcriptomic Influences on Heparin-Induced Thrombocytopenia

基因组和转录组对肝素诱导的血小板减少症的影响

• 批准号: 9899307
• 负责人: Jason Hansen Karnes
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899307
• 关键词: Address; Adverse drug effect; Adverse reactions; Alleles; Antibodies; Antibody Formation; Anticoagulants; Award; Big Data; Bioinformatics; Biological; Biological Assay; Biological Markers; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Cells; Clinical; Clinical Research; Clinical Treatment; Complement; DNA Resequencing; Data; Development; Diagnostic; Exposure to; Fostering; Foundations; Future; Genes; Genomics; Goals; Heparin; Immune; Incidence; Individual; Investigation; Knowledge; Life; Mediating; Mission; Molecular; PF4 Gene; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacogenomics; Pharmacy facility; Platelet Activation; Prevention; Prevention strategy; Preventive; Production; Public Health; Reaction; Research; Research Personnel; Resources; Role; T-Cell Activation; T-Cell Activation Pathway; Techniques; Testing; Thromboembolism; Training; Translating; United States National Institutes of Health; Up-Regulation; Variant; Work; adverse drug reaction; base; blood group; career; career development; clinical practice; clinical predictors; clinical translation; cohort; direct application; experience; genetic association; genome wide association study; genomic variation; heparin-induced thrombocytopenia; immunopathology; innovation; insight; mortality; novel; novel strategies; precision medicine; skills; tool; transcriptome sequencing; transcriptomics

ABSTRACT Despite decades of research into the immunopathology of heparin-induced thrombocytopenia (HIT), an unpredictable, life-threatening, immune-mediated adverse reaction to heparin treatment, a fundamental knowledge gap regarding the cause of HIT remains. The inability to predict HIT represents a considerable liability associated with heparin administration. Because the exact cellular and molecular mechanisms underlying HIT have yet to be identified, including the impetus for antibody production and critical immune cell roles, there is an essential need to apply alternative approaches to understand the biological basis for HIT and to identify clinically implementable biomarkers. The research objective of this proposal is to determine the role of genomic and transcriptomic variation in HIT pathogenesis. The PI's central hypothesis is that variation in genomic and transcriptomic pathways impacts HIT pathogenesis and can be used to identify clinically implementable HIT biomarkers. Based on strong preliminary data that constitute the first genome-wide association study (GWAS) and N-of-1 pathways studies for HIT, the working hypothesis is that the upregulation of T cell activation pathways results in PF4/heparin antibody production and that histo-blood group gene ABO O alleles subsequently result in HIT through platelet activation. We will pursue two Specific Aims (SAs) to test the central hypothesis: (1) determine the influence of genomic variation on HIT and (2) identify transcriptomic pathways involved in HIT pathogenesis using an N-of-1 strategy. In SA #1, a GWAS and gene resequencing approach will be utilized to identify genetic associations with HIT and platelet factor 4 (PF4)/heparin antibody production. In SA #2, peripheral blood mononuclear cells (PBMCs) will be collected and RNA-Seq will be performed. The N- of-1 pathways approach will be utilized to determine up- and down-regulated transcriptomic pathways involved in HIT and in the development of PF4/heparin antibodies. The proposed research has the potential to garner significant insights into HIT pathogenesis and to provide a framework for the clinical translation of HIT biomarkers into early diagnostic and preventive strategies. The proposed studies are technically innovative as they leverage novel strategies for large-scale biological data, including the N-of-1 pathways approach, and because establishing tools to distinguish patients that are pre-disposed to HIT could potentially shift current clinical practice paradigms. The PI's career development objective is to acquire expertise in bioinformatics and the research tools necessary to address his long-term research goal, including experience in big data, genomic and transcriptomic pathways, and innovative clinical study approaches. The knowledge and skills garnered during this award will provide foundational training and resources for future work in pharmacogenomics, facilitate eventual submission of an R01 proposal, and foster the transition to an independent researcher investigating adverse reactions to cardiovascular drugs.

抽象的 尽管对肝素诱导的血小板减少症 (HIT) 的免疫病理学进行了数十年的研究，但 肝素治疗的不可预测的、危及生命的、免疫介导的不良反应是肝素治疗的一个根本原因 关于 HIT 成因的知识差距仍然存在。无法预测 HIT 意味着相当大的责任 与肝素给药有关。因为 HIT 背后的确切细胞和分子机制 尚未确定，包括抗体产生的推动力和关键的免疫细胞作用，有一个 迫切需要应用替代方法来了解 HIT 的生物学基础并在临床上进行识别 可实施的生物标志物。该提案的研究目标是确定基因组和 HIT 发病机制中的转录组变异。 PI 的中心假设是基因组和 转录组通路影响 HIT 发病机制，可用于识别临床上可实施的 HIT 生物标志物。基于构成第一个全基因组关联研究 (GWAS) 的强有力的初步数据 和 HIT 的 N-of-1 途径研究，工作假设是 T 细胞激活的上调 途径导致 PF4/肝素抗体产生，并且组织血型基因 ABO O 等位基因 随后通过血小板激活导致 HIT。我们将追求两个具体目标（SA）来测试中央 假设：(1) 确定基因组变异对 HIT 的影响；(2) 确定转录组通路 使用 N-of-1 策略参与 HIT 发病机制。在 SA #1 中，GWAS 和基因重测序方法将 可用于鉴定与 HIT 和血小板因子 4 (PF4)/肝素抗体产生的遗传关联。在 SA #2，将收集外周血单核细胞 (PBMC) 并进行 RNA 测序。然后- of-1 途径方法将用于确定所涉及的上调和下调转录组途径 HIT 和 PF4/肝素抗体的开发。拟议的研究有可能获得 对 HIT 发病机制的重要见解并为 HIT 生物标志物的临床转化提供框架 纳入早期诊断和预防策略。拟议的研究在技术上具有创新性，因为它们利用了 大规模生物数据的新策略，包括 N-of-1 路径方法，并且因为 建立工具来区分易患 HIT 的患者可能会改变当前的临床 实践范式。 PI 的职业发展目标是获得生物信息学和 实现其长期研究目标所需的研究工具，包括大数据、基因组和 转录组途径和创新的临床研究方法。期间获得的知识和技能 该奖项将为药物基因组学的未来工作提供基础培训和资源，促进 最终提交 R01 提案，并促进向独立研究人员调查的过渡 心血管药物的不良反应。