Validation of a Genetic-based Biomarker Panel for Stratification of Mortality Risk in ARDS Patients

用于 ARDS 患者死亡风险分层的基于基因的生物标志物组的验证

• 批准号: 10645784
• 负责人: Christian Bime
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645784
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Angiopoietin-2; Attenuated; Biological Assay; Biological Markers; Black Populations; COVID-19 pandemic; COVID-19 pneumonia; COVID-19/ARDS; Clinical Trials; Clinical Trials Design; Data; Early treatment; Evaluation; FDA approved; Failure; Future; Genes; Genetic; Genomics; Genotype; Grant; Heterogeneity; Human; IL8 gene; Immunoglobulins; Induction of neuromuscular blockade; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Letters; Leukocyte Trafficking; Ligands; Lung; Mediation; Mendelian randomization; Modeling; Molecular; Monoclonal Antibodies; National Heart, Lung, and Blood Institute; Niacinamide; Outcome; P-Selectin; P-selectin ligand protein; Participant; Patients; Pattern; Pharmacogenetics; Phenotype; Plasma; Platelet aggregation; Predisposition; Prevention; Proteins; Pulmonary Inflammation; Risk; SELP gene; Sampling; Selectins; Sepsis; Severities; Signal Pathway; Stratification; TLR4 gene; Therapeutic; Therapeutic Clinical Trial; Thrombosis; Transferase; Validation; Variant; anakinra; biomarker panel; clinically relevant; design; extracellular; genetic variant; health disparity; improved; innovation; insight; lung injury; member; mortality; mortality risk; multiorgan injury; neutralizing monoclonal antibodies; novel; novel marker; novel therapeutics; patient stratification; pharmacologic; point of care; pre-clinical; predictive marker; predictive test; radiological imaging; systemic inflammatory response; therapeutic target; tool

PROJECT SUMMARY: The COVID-19 pandemic has dramatically highlighted serious unmet needs of ARDS including the absence of effective FDA-approved pharmacologic interventions that address ARDS mortality. ARDS phenotype heterogeneity, the complexity of dysregulated inflammation, and the absence of predictive biomarkers have all contributed to failed ARDS therapeutic clinical trials. Predictive biomarkers, either protein- or genomic-based, that identify specific ARDS sub-phenotypes and likely responders to specific ARDS therapeutics, could significantly influence effective clinical trial designs to assess novel therapeutics and therefore benefit the outcomes of ARDS trials. Our group has long championed the utility of genomic-intensive approaches to identify multiple novel ARDS therapeutic targets. We previously identified eNAMPT (extracellular nicotinamide phosphoribosyl transferase) as a novel ARDS therapeutic target/gene which serves as a damage-associated molecular pattern protein (DAMP) and ligand for Toll-like receptor 4 (TLR4). NAMPT SNPs predict ARDS severity and eNAMPT amplifies dysregulated lung/systemic inflammatory responses that contribute to multi- organ injury/failure. We demonstrated the utility of a humanized eNAMPT-neutralizing mAb as a therapeutic strategy in ARDS and other inflammatory conditions. Plasma eNAMPT, along with IL-6, IL-8, IL-1RA, MIF, and Ang-2, was highly predictive of 28-day ARDS mortality. We also identified variants in selectin P ligand gene (SELPLG) encoding P-selectin glycoprotein ligand 1 (PSGL1), and P-selectin gene (SELP) as associated with increased susceptibility to ARDS in Blacks. PSGL1/P-selectin interactions are critical to lung inflammation via leukocyte trafficking, platelet aggregation, and thrombosis. Plasma PSGL1 and P-selectin levels are significantly elevated in sepsis, ARDS, and COVID-19 pneumonia patients and PSGL1 inhibition (mAb, TSGL-Ig) significantly attenuates preclinical lung injury in ARDS. This R-21 application will utilize over 900 plasma samples and genotyping results available from the NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Reevaluation of systemic Early neuromuscular blockade (ROSE) study (see NHLBI BioLINCC letter). We will validate two highly novel stratification tools to improve patient stratification in the design of future ARDS clinical trials targeting eNAMPT/TLR4 and PSGL1/P-Selectin interactions. Specific Aim (SA) #1 will develop a genotype-based biomarker assay combining: i) carefully selected SELPLG/SELP variants with plasma PSGL1/P-selectin levels, and ii) NAMPT variants with plasma eNAMPT levels. These genotypes will identify ARDS subjects as candidates for future clinical trials targeting PSGL-1/P-selectin interactions and the eNAMPT/TLR4 signaling pathway. SA #2 will validate the predictive capacity of a seven-biomarker panel (eNAMPT, IL-6, IL-8, IL-1RA, PSGL-1, IL-1β, Ang-2) for ARDS mortality. Successful completion of this highly innovative R21 grant will generate a novel ‘point of care’ pharmacogenetic enrichment tools to be leveraged in designing human ARDS clinical trials targeting PSGL1/P-selectin and eNAMPT/TLR4 interactions.

项目摘要： 19009年大流行极大地强调了ARDS的严重未满足的需求，包括没有 有效的FDA批准的药学干预措施解决了ARDS死亡率。 ARDS表型 异质性，感染失调的复杂性和缺乏预测性生物标志物具有所有 导致ARDS治疗临床试验失败。预测性生物标志物，无论是蛋白质还是基因组， 确定特定的ARDS子表型和可能对特定ARDS治疗的反应者，可以 显着影响有效的临床试验设计，以评估新型治疗，因此有益于 ARDS试验的结果。我们的小组长期以来一直倡导基因组密集型方法的实用性 多个新型ARDS治疗靶标。我们先前鉴定了ENAMPT（细胞外烟酰胺 磷酸贝糖基转移）作为一种新型的ARDS治疗靶/基因，作为损伤相关 分子图案蛋白（湿）和指控受体4（TLR4）的配体。 NAMPT SNP预测ARDS 严重程度和ENAMPT放大器失调的肺部/全身性炎症反应，导致多种作用 器官损伤/故障。我们证明了人源化的陶器中和mab作为一种疗法的实用性 ARDS和其他炎症条件中的策略。等离子体ENAMPT，以及IL-6，IL-8，IL-1RA，MIF和 Ang-2高度预测了28天的ARDS死亡率。我们还确定了选择素P配体基因中的变体 （SELPLG）编码p-选择蛋白糖蛋白配体1（PSGL1）和p-选择蛋白基因（SELP） 黑人对ARDS的敏感性增加。 PSGL1/P-选择素相互作用对于通过 白细胞运输，血小板聚集和血栓形成。等离子体PSGL1和P-选择素水平显着 败血症，ARD和Covid-19肺炎患者和PSGL1抑制作用（MAB，TSGL-Ig）升高显着升高 减轻ARDS临床前肺损伤。该R-21应用程序将使用900多个等离子体样本，并且 NHLBI预防和急性肺损伤的早期治疗可获得的基因分型结果（Petal） 全身性神经肌肉封锁（ROSE）研究的网络重新评估（请参阅NHLBI Biolincc字母）。 我们将验证两个高度新颖的分层工具，以改善未来ARD的设计中的患者分层 针对ENAMPT/TLR4和PSGL1/P-选择素相互作用的临床试验。特定目标（SA）＃1将发展 基于基因型的生物标志物测定：i）精心选择的SELPLG/SELP变体与等离子体 PSGL1/P-选择素水平和II）具有血浆ENAMPT水平的NAMPT变体。这些基因型将确定 ARDS受试者作为针对PSGL-1/P-选择素相互作用的未来临床试验的候选者 ENAMPT/TLR4信号通路。 SA＃2将验证七个生物标记面板的预测能力 （ENAMPT，IL-6，IL-8，IL-1RA，PSGL-1，IL-1β，ANG-2）用于ARDS死亡率。成功完成了这个 创新的R21 Grant将产生一种新颖的“护理点”药物富集工具，以利用 在设计针对PSGL1/P-选择素和ENAMPT/TLR4相互作用的人类ARDS临床试验时。