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，在转化挫伤扩张机制的临床前工作方面一直存在着重大差距 创伤性脑损伤 (TBI) 中的临床治疗可改善结果。这很重要，因为挫伤 扩张是 TBI 不良结果的主要驱动因素，发病率和死亡率增加高达 5 倍，但 没有治疗方法或生物标志物可以识别处于危险中的患者。解决这个问题有巨大的潜力 问题是因为与原发性损伤不同，挫伤扩张是由宿主对初始 TBI 的反应引起的，因此 是一种可改变的继发性伤害。基于指南的护理使用反应性模板方法来解决这一问题 复杂的过程，没有解决贡献途径的个体差异；它不会阻止或限制 挫伤扩大并努力减轻危及生命的后果。这种同质化的策略 毫不奇怪，针对异质性疾病的研究导致了许多临床试验的失败。我们的长期目标是 利用相关的个人数据（分子、单细胞 [SC]、遗传、成像）来指导精准医疗 TBI挫伤扩大。 R21 弥补了一种有前途的挫伤疗法中现有的知识空白 正在准备翻译的扩展：格列本脲（GLY）。现有的研究产生了令人兴奋的势头，但 还揭示了 GLY 靶标的主要个体差异，可能影响药物反应/成功翻译。 我们的目标是使用 SC 和蛋白质组学策略对 GLY 靶向途径进行分子内型分析 人类 TBI 中的挫伤扩张。理由是它可以让我们更好地理解异质性的好处 GLY 和优化翻译的机会：它告知关键可定位和可测量的细胞起源 挫伤扩张途径。中心假设是可量化的细胞类型特异性的子集 GLY 靶向的差异表达基因、通路和蛋白质可识别 TBI 挫伤扩展的风险。 目标 1 证明脑脊液 (CSF) SC 转录组特征内型 GLY 靶向 人体挫伤扩张。目标 2 表明挫伤扩张先于 GLY 靶向 蛋白质生物标志物发生变化。这些目标是协同的：细胞类型差异基因表达（目标 1）提供信息 挫伤扩张的可测量脑脊液生物标志物（目标 2）的可能来源。这项工作是可行的，因为令人兴奋 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管道。这是 创新，因为它将基于指南的方法转变为精准医学，创建了第一个人体脑脊液图集 TBI 中的 SC 反应，并识别正在测试的药物靶向途径中的挫伤扩张生物标志物 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 GLY 试验的选择（高风险、药效学反应）。导致挫伤的独特细胞成分 扩展与早期临床可测量的脑脊液生物标志物相结合可以指导前所未有的细胞和靶标 精确治疗，包括新颖的（预防性）药物靶点。这为范式转变奠定了基础 基于 SC 的精准医学方法，用于了解、监测和治疗 TBI 中毁灭性的继发性损伤。