A Translational Evaluation of Sur1-Trpm4 Imaging Endophenotypes and Genetics to Direct Precision Medicine for Cerebral Edema After Traumatic Brain Injury

Sur1-Trpm4 成像内表型和遗传学的转化评估指导精准医学治疗脑外伤后脑水肿

• 批准号: 10117587
• 负责人: Ruchira Menka Jha
• 金额: $ 57万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-05 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117587
• 关键词: Address; Affect; Brain; Brain Edema; Brain Injuries; Brain region; Caring; Cations; Cause of Death; Cells; Cerebral Edema; Cerebral Edema Management; Cerebrum; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Complex; Contusions; Cost of Illness; Data; Diagnostic radiologic examination; Diffuse; Disease; Edema; Evaluation; Foundations; Future; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Glyburide; Goals; Growth; Guidelines; Heterogeneity; Human; Hypotension; Ideal 1; Image; Individual; Individual Differences; Injury; International; Intervention; Intracranial Pressure; Knock-in Mouse; Knock-out; Knowledge; Link; Magnetic Resonance Imaging; Maps; Measurable; Measures; Methodology; Mission; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Outcome; Pathway Analysis; Pathway interactions; Patient Selection; Patient risk; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Preventive; Probability; Process; Prognosis; Property; Proteins; Protocols documentation; Research; Research Personnel; Resources; Risk; SNP genotyping; Single Nucleotide Polymorphism; Sodium; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Traumatic Brain Injury; Validation; Variant; Water; Work; base; causal variant; cell type; clinical care; clinical translation; clinically relevant; cohort; controlled cortical impact; design; disability; early phase clinical trial; effective therapy; endophenotype; fluid percussion injury; high risk; improved; improved outcome; in vivo evaluation; individual variation; innovation; molecular imaging; molecular phenotype; molecular targeted therapies; mouse model; nervous system disorder; novel; operation; patient stratification; phase II trial; potential biomarker; pre-clinical; precision medicine; preclinical study; prevent; protein expression; receptor; response; risk stratification; sulfonylurea receptor; targeted therapy trials; targeted treatment; therapeutic target; tool; treatment optimization; treatment response; trial design

For decades, there has been a critical gap in translating preclinical work on mechanisms of cerebral edema in traumatic brain injury (TBI) to clinically available targeted therapies that improve outcome. This is important because cerebral edema management commands substantial clinical and financial resources in severe TBI, yet it remains a common cause of death and disability. Current treatments are indiscriminate, reactionary and morbid - none improve outcome. Guideline-based protocols use a templated approach to this immensely complex process without addressing individual differences in contributory pathways or edema endophenotypes. The long -term goal is to harness relevant individual data (genetic, molecular, imaging, physiologic) to direct a precision medicine approach to treat TBI edema and related contusion expansion. This R01 focuses on logical next steps to address existing knowledge gaps in a unique, key edema pathway involving Sulfonylurea receptor-1 (Sur1) and its regulated cation channel Trpm4. Promising results from Sur-1 inhibition (Glyburide, GLY) in preclinical and early clinical brain injury trials have generated exciting momentum in this pathway. The objective of this translational R01 is to define the impact of Sur1-Trpm4 related genetic and protein variability on different edema endophenotypes, contusion growth and response to inhibition in preclinical and human TBI. The rationale is that identifying these individual differences directly informs patient risk-stratification, prognosis, trial design, and targeted therapy; ultimately improving outcome. The central hypothesis is that Sur1 protein expression and genetic variability influence the endophenotype, extent, and therapeutic response of TBI edema. Aim 1 defines correlations between Sur1-Trpm4 expression and MRI edema endophenotypes in three clinically relevant complementary mouse models. Aim 2 tests effects of Sur1 inhibition (GLY, inducible knockout) in these models on MRI edema endophenotypes, contusion, and outcome. Aim 3 identifies impact of genetic variation in the Sur1 pathway on TBI edema and contusion growth (on imaging) in a single-center human test-cohort, and a multicenter validation-cohort. The work is feasible as shown by robust preliminary results and the tools, expertise and track record of successful collaborations among coinvestigators. This work is innovative in concept and methodology: it shifts a guideline-based paradigm toward precision medicine, links clinically measurable edema endophenotypes (MRI) with a molecular pathway and targeted inhibition in different TBI models, and uses a novel transgenic mouse to generate Sur1-Trpm4 expression maps. This research is significant, with high impact if successful: linking Sur1-Trpm4 expression and inhibition to MRI endophenotypes (Aims 1-2) directly translate to identifying appropriate patients for targeted therapy and trials. Distinguishing high vs low risk genetic profiles (Aim-3) will identify patients in whom Sur1-Trpm4 is a major contributor to TBI edema and contusion growth, and channel inhibition may be highly beneficial- directing clinical care and trials. Ultimately, such knowledge has the potential to transform precision-medicine care of this devastating secondary injury and improve TBI outcome.

几十年来，在翻译关于脑水肿机制的临床前工作方面一直存在严重的差距 创伤性脑损伤(TBI)是临床上可用的改善结果的靶向治疗方法。这事很重要 因为在重型颅脑损伤中，脑水肿的处理需要大量的临床和财政资源，但 它仍然是导致死亡和残疾的常见原因。目前的治疗方法是不加区别的、反动的和病态的。 -没有一个能改善结果。基于指南的协议使用模板化的方法来处理这一极其复杂的问题 过程中没有解决的贡献途径或水肿内表型的个体差异。《长河》 -长期目标是利用相关的个人数据(遗传、分子、成像、生理)来指导精确 治疗颅脑损伤水肿及相关挫伤扩张症的药物途径。本R01侧重于合乎逻辑的后续步骤 解决涉及磺脲类药物受体-1(Sur1)的独特、关键的水肿途径中存在的知识缺口 及其调控的阳离子通道Trpm4。在临床前抑制SUR-1(格列本脲，Gly)的有希望的结果 早期的临床脑损伤试验已经在这一途径上产生了令人兴奋的势头。这样做的目的是 翻译R01是为了确定Sur1-Trpm4相关的基因和蛋白质变异对不同水肿的影响 临床前和人类脑外伤的内表型、挫伤生长和对抑制的反应。理由是 识别这些个体差异直接告知患者风险分层、预后、试验设计和 有针对性的治疗；最终改善结果。中心假设是Sur1蛋白的表达和 遗传变异影响脑外伤后水肿的内表型、程度和治疗反应。目标1定义 三种临床相关组织中Sur1-Trpm4的表达与MRI水肿内表型的相关性 互补的小鼠模型。目的2检测Sur1抑制(GLY，可诱导基因敲除)在这些模型中的作用 在MRI上，水肿的内表型、挫伤和预后。目标3确定Sur1基因变异的影响 在单中心人类试验队列中，脑外伤水肿和挫伤生长的途径(在成像上)，以及 多中心验证-队列。稳健的初步结果以及工具和专业知识表明，这项工作是可行的 以及协查人员之间成功合作的记录。这项工作在理念和方法上具有创新性。 方法：它将以指南为基础的范式转向精准医学，将临床可测量的水肿联系起来 在不同的脑损伤模型中，具有分子途径和靶向抑制的内表型(MRI)，并使用 构建Sur1-Trpm4表达图谱的新型转基因小鼠。这项研究意义重大，影响很大 如果成功：将Sur1-Trpm4的表达和抑制与MRI内表型(AIMS 1-2)直接翻译 寻找合适的患者进行靶向治疗和试验。区分高风险和低风险基因图谱 (AIM-3)将确定Sur1-Trpm4是导致脑损伤水肿和挫伤生长的主要因素的患者，以及 抑制通道可能是非常有益的--指导临床护理和试验。归根结底，这种知识具有 有可能改变这种毁灭性的继发性损伤的精确医疗护理，并改善颅脑损伤的预后。