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: 10401300
• 负责人: Ruchira Menka Jha
• 金额: $ 57.35万
• 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/10401300
• 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; 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; Persons; 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; radiological imaging; 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，在将关于脑水肿机制的临床前工作转化为脑水肿的临床前工作方面， 创伤性脑损伤（TBI）的临床可用的靶向治疗，改善结果。这很重要 因为脑水肿的治疗需要大量的临床和财政资源， 它仍然是造成死亡和残疾的常见原因。目前的治疗是不分青红皂白的，反动的和病态的 - 没有改善结果。基于指南的协议使用模板化的方法来处理这个极其复杂的 在没有解决贡献途径或水肿内表型的个体差异的情况下，长 - 长期目标是利用相关的个体数据（遗传，分子，成像，生理）来指导精确的 治疗TBI水肿和相关挫伤扩大的药物方法。此R 01侧重于逻辑后续步骤 解决涉及磺酰脲受体-1（Sur 1）的独特关键水肿途径中的现有知识缺口 及其调节的阳离子通道Trpm 4。Sur-1抑制（格列本脲，GLY）在临床前的有希望的结果 早期临床脑损伤试验已经在这一途径中产生了令人兴奋的动力。的目的 翻译R 01是为了定义Sur 1-Trpm 4相关的遗传和蛋白变异性对不同水肿的影响， 内表型、挫伤生长和对临床前和人TBI抑制的反应。基本原理是 识别这些个体差异直接告知患者风险分层、预后、试验设计， 靶向治疗;最终改善结果。中心假设是Sur 1蛋白表达和 遗传变异性影响TBI水肿的内表型、程度和治疗反应。目标1定义 Sur 1-Trpm 4表达与MRI水肿内表型之间的相关性 互补的小鼠模型。目的2在这些模型中测试Sur 1抑制（GLY，诱导型敲除）的效果 MRI水肿内表型、挫伤和结局。目的3确定Sur 1中遗传变异的影响 在单中心人类测试队列中TBI水肿和挫伤生长（成像）的途径，以及 多中心验证队列。这项工作是可行的，因为强大的初步结果和工具，专业知识 以及共同研究者之间成功合作的记录。这项工作在概念上是创新的， 方法学：它将基于指南的范式转变为精确医学，将临床可测量的水肿 内表型（MRI）与分子途径和靶向抑制在不同的TBI模型，并使用 新的转基因小鼠产生Sur 1-Trpm 4表达图谱。这项研究意义重大，影响巨大 如果成功：将Sur 1-Trpm 4表达和抑制与MRI内表型联系起来（目的1-2） 为靶向治疗和试验寻找合适的患者。区分高风险与低风险遗传特征 （目标-3）将确定Sur 1-Trpm 4是TBI水肿和挫伤生长的主要原因的患者，以及 通道抑制可能是非常有益的-指导临床护理和试验。最终，这些知识 有可能改变这种毁灭性的继发性损伤的精确医学护理，并改善TBI的结果。