A Single Cell and Proteomic Precision Medicine Approach to Glyburide Responsive Contusion Expansion in Severe Traumatic Brain Injury

单细胞和蛋白质组精准医学方法治疗严重创伤性脑损伤中的格列本脲反应性挫伤扩张

• 批准号: 10645458
• 负责人: Ruchira Menka Jha
• 金额: $ 25.2万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645458
• 关键词: Acute; Address; Affect; Atlases; Biological Markers; Brain; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Clinical Trials; Complex; Contusions; Custom; Data; Detection; Development; Disease; Economic Burden; Foundations; Frequencies; Future; Genes; Genetic; Glyburide; Goals; Guidelines; Heterogeneity; Human; Image; Immune response; Individual; Individual Differences; Injury; Knowledge; Life; Link; Measurable; Mission; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; National Institute of Neurological Disorders and Stroke; Neurosciences; Outcome; Participant; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Prevention strategy; Preventive; Process; Prospective cohort; Proteins; Proteomics; Research; Risk; Sampling; Selection for Treatments; Signal Pathway; Societies; Source; TBI treatment; Testing; Tissue-Specific Gene Expression; Translating; Translations; Traumatic Brain Injury; Work; X-Ray Computed Tomography; biobank; bioinformatics pipeline; biomarker identification; cell type; computational pipelines; differential expression; disability; disease heterogeneity; druggable target; first-in-human; genetic signature; genetic variant; health economics; high risk; improved outcome; innovation; mild traumatic brain injury; mortality; multidisciplinary; nervous system disorder; new therapeutic target; novel; patient stratification; pre-clinical; precision medicine; prevent; protein biomarkers; response; response biomarker; risk stratification; single-cell RNA sequencing; standard care; sulfonylurea receptor; targeted treatment; therapeutic target; transcriptome; transcriptomics; trial design

For decades, there has been a critical gap in translating preclinical work on mechanisms of contusion expansion in traumatic brain injury (TBI) to clinical therapies that improve outcome. This is important because contusion expansion is a major driver of unfavorable outcome in TBI with up to 5X increase in morbidity and mortality, yet there are no treatments or biomarkers to identify patients at risk. There is immense potential to address this issue because unlike primary injury, contusion expansion results from host response to the initial TBI and thus is a modifiable secondary injury. Guideline-based care uses a reactive templated approach to this hugely complex process without addressing individual differences in contributory pathways; it does not prevent or limit contusion expansion and struggles to mitigate the life-threatening consequences. Such homogeneous strategies for a heterogeneous disease have unsurprisingly led to many failed clinical trials. Our long-term goal is to harness relevant individual data (molecular, single-cell [SC], genetic, imaging) to direct precision medicine for TBI contusion expansion. This R21 addresses existing knowledge gaps in a promising therapy for contusion expansion being primed for translation: Glyburide (GLY). Existing research generated exciting momentum but also revealed major individual differences in GLY targets that could affect drug-response/successful translation. Our objective is to use SC and proteomic strategies to molecularly endotype GLY-targeted pathways of contusion expansion in human TBI. The rationale is that it allows us to better understand heterogeneous benefits and opportunities of GLY and optimize translation: it informs cellular origins of key targetable and measurable contusion expansion pathways. The central hypothesis is that a subset of quantifiable cell-type specific differentially expressed genes, pathways and proteins targeted by GLY identify risk for TBI contusion expansion. Aim 1 demonstrates that cerebrospinal fluid (CSF) SC transcriptomic signatures endotype GLY-targeted contusion expansion in humans. Aim 2 demonstrates that contusion expansion is preceded by GLY-targetable protein biomarkers changes. The aims are synergistic: cell-type differential gene expression (Aim 1) informs likely sources of measurable CSF biomarkers (Aim 2) of contusion expansion. The work is feasible given exciting pilot data, an existing TBI biobank, an established multidisciplinary team and bioinformatic pipelines. It is innovative as it shifts a guideline-based approach to precision medicine, creates a first-in-human atlas of CSF SC response in TBI, and identifies contusion expansion biomarkers in pathways targeted by a drug being tested in human TBI. The expected impact includes molecular endotype-based risk-stratification and enriched patient- selection for GLY trials (high risk, pharmacodynamic response). Unique cellular components that drive contusion expansion combined with early clinically measurable CSF biomarkers can guide unprecedented cell- and target- precise therapy including novel (preventive) druggable targets. This lays the foundation for a paradigm shifting SC-based precision medicine approach to understand, monitor, and treat a devastating secondary injury in TBI.

几十年来，翻译有关挫伤扩张机制的临床前工作一直存在关键的差距 在脑外伤（TBI）中，可改善预后的临床疗法。这很重要，因为挫伤 扩张是TBI不利结果的主要驱动力，发病率和死亡率高达5倍，但 没有治疗或生物标志物来识别有危险的患者。有巨大的潜力解决这个问题 问题是因为与原发性损伤不同，挫伤扩展是宿主对初始TBI的反应，因此 是可修改的继发损伤。基于指南的护理使用反应性模板方法来极大地 复杂的过程，而无需解决贡献途径的个体差异；它不能阻止或限制 挫伤扩张和努力减轻威胁生命的后果。这种均匀的策略 对于异质性疾病而言，毫不奇怪地导致了许多临床试验失败。我们的长期目标是 线束相关的个体数据（分子，单细胞[SC]，遗传，成像），以指导精确医学 TBI挫伤扩展。此R21解决了有希望的挫伤疗法中现有的知识差距 扩展是用于翻译的：格利伯（Gly）。现有研究产生了令人兴奋的动力，但 还揭示了可能影响药物反应/成功翻译的GLY靶标的主要个体差异。 我们的目的是使用SC和蛋白质组学策略来分子内型Gly靶向的途径 人类TBI的挫伤扩张。理由是它使我们能够更好地理解异质的好处 Gly和优化翻译的机会：它为关键目标和可测量的关键的细胞起源提供了信息 挫伤扩展途径。中心假设是可量化的细胞类型特异性的子集 GLY靶向的差异表达的基因，途径和蛋白质鉴定了TBI挫伤膨胀的风险。 AIM 1证明了脑脊液（CSF）SC转录组特征内型Gly-targetter 人类的挫伤扩张。 AIM 2表明，挫伤扩张之前是可以靶向的 蛋白质生物标志物变化。目的是协同的：细胞类型差异基因表达（AIM 1）告知 可能可测量的CSF生物标志物（AIM 2）的可能来源的挫伤膨胀。这项工作令人兴奋，这是可行的 试点数据，现有的TBI生物库，已建立的多学科团队和生物信息学管道。这是 创新性，因为它改变了基于准则的精确医学方法，因此创建了CSF的第一个人类地图集 TBI中的SC响应，并鉴定通过测试药物靶向的途径的挫伤膨胀生物标志物 在人类TBI中。预期的影响包括基于分子内型的风险分层和丰富的患者 - 选择GLY试验（高风险，药效反应）。驱动挫伤的独特蜂窝组件 扩张与早期临床可测量的CSF生物标志物相结合可以指导前所未有的细胞和靶标。 精确的疗法，包括新颖的（预防性）可药靶标。这为范式转移奠定了基础 基于SC的精确医学方法可以理解，监测和治疗TBI毁灭性的继发损伤。