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，翻译有关脑水肿机制的临床前工作一直存在关键的差距 创伤性脑损伤（TBI）对改善预后的临床可用靶向疗法。这很重要 因为脑水肿管理在严重的TBI中指挥大量临床和财务资源 它仍然是死亡和残疾的普遍原因。当前的治疗是不加区分的，反动和病态的 - 没有改善结果。基于指南的协议使用模板方法来实现这一非常复杂的方法 过程中没有解决促进途径或水肿内表型的个体差异的过程。长 - 期限是利用相关的个人数据（遗传，分子，成像，生理学）来指导精度 治疗TBI水肿和相关挫伤扩张的医学方法。此R01专注于逻辑下一步 在涉及磺酰脲受体1（SUR1）的独特的关键水肿途径中解决现有知识差距（SUR1） 及其受调节的阳离子通道TRPM4。 SUR-1抑制（Glyburide，Gly）在临床前的有希望的结果 早期的临床脑损伤试验在这一途径中产生了令人兴奋的动力。这个目的 转化R01是定义SUR1-TRPM4相关遗传和蛋白质变异性对不同水肿的影响 临床前和人类TBI中的内表型，挫伤生长和对抑制作用的反应。理由是 确定这些个体差异直接告知患者风险分层，预后，试验设计和 靶向治疗；最终改善结果。中心假设是SUR1蛋白表达和 遗传变异影响TBI水肿的内表型，程度和治疗反应。 AIM 1定义 SUR1-TRPM4表达与三种临床相关的MRI水肿内表型之间的相关性 互补的鼠标模型。在这些模型中，AIM 2测试SUR1抑制作用（GLY，诱导敲除） 关于MRI水肿内表型，挫伤和结果。 AIM 3标识了SUR1遗传变异的影响 单中心的人类测试局中的TBI水肿和挫伤生长（成像）的途径，A 多中心验证库。强大的初步结果和工具，专业知识所示，这项工作是可行的 并记录了共同评估者之间成功合作的记录。这项工作在概念上具有创新性和 方法论：它将基于指南的范式转移到精确医学，链接临床可测量的水肿 具有分子途径并在不同TBI模型中靶向抑制的内表型（MRI），并使用 新型转基因小鼠生成SUR1-TRPM4表达图。这项研究很大，影响很大 如果成功：将SUR1-TRPM4表达和抑制与MRI内表型联系起来（AIMS 1-2）直接翻译 识别适当的患者进行有针对性的治疗和试验。区分高风险遗传概况 （AIM-3）将确定SUR1-TRPM4的患者是造成TBI水肿和挫伤生长以及 通道抑制可能是非常有益的临床护理和试验。最终，这样的知识具有 改变这种毁灭性的继发损伤并改善TBI结果的潜力。