Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

表观遗传标记和持续细胞保护用于中风治疗

• 批准号: 9340960
• 负责人: Keith Booher
• 金额: $ 22.5万
• 依托单位: ZYMO RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340960
• 关键词: Acute; Adverse effects; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain hemorrhage; Brain-Derived Neurotrophic Factor; Clinical; Collaborations; Cytoprotection; DNA; DNA Methylation; DNA analysis; Data Analyses; Deterioration; Diffusion; Epigenetic Process; Evaluation; Frequencies; Gases; Genes; Genomics; Goals; Health Sciences; Hospitals; Injury; International; Intervention; Investigation; Ischemic Stroke; Legal patent; Liposomes; Long-Term Effects; Mediating; Methods; Neuroglia; Neurologic Dysfunctions; Neurons; Pathologic; Patients; Phase; Phenotype; Phosphorylation; Phosphotransferases; Play; Prevention; Process; Protocols documentation; Recovery; Research; Research Personnel; Resolution; Role; Sampling; Site; Small Business Technology Transfer Research; Source; Stimulus; Stroke; Subarachnoid Hemorrhage; Technology; Texas; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Treatment Efficacy; Tropomyosin; Universities; Xenon; brain tissue; cerebral ischemic injury; commercialization; conditioning; critical period; epigenetic marker; epigenetic regulation; experience; genome-wide; genome-wide analysis; hypoxia inducible factor 1; improved; liposomal delivery; mortality; neuroprotection; neurovascular; novel; novel therapeutics; post stroke; prevent; protective effect; receptor; response; stroke treatment; therapeutic candidate

PROJECT SUMMARY/ABSTRACT Stroke injury is a process that occurs over a long duration with pathologic changes that result in long-term neurologic dysfunction. For stroke, there exists an important need for a strategy that can provide safe and efficacious stabilization to the hypoperfused brain and initialize long-lasting endogenous neuroprotection for prevention of long-term neurologic dysfunction. Sufficient evidence has shown that xenon (Xe), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the blood-brain barrier (BBB) with minimal side effects. In recent novel studies, researchers at The University of Texas Health Science Center at Houston (UTHealth) incorporated Xe into liposomes and demonstrated that Xe-liposome treatment post-stroke resulted in activation of endogenous brain protection following ischemic stroke and subarachnoid hemorrhage. Corroborated mechanisms of Xe cytoprotection include the activation of endogenous cytoprotective molecules. Repetitive administration of Xe-liposomes extends the protective effects over time. Although the detailed mechanisms underlying repetitive administration induced long-term protection remain unclear, emerging evidence supports that such adaptive phenotypes are epigenetically mediated. As epigenetic post-conditioning is highly related to the potency, frequency and duration of stimuli, we hypothesize that repetitive intermittent Xe- liposomal administration at an optimal frequency and duration can induce epigenetic post-conditioning resulting in long-term effects. This hypothesis leads to the collaboration between Zymo Research Corporation (Zymo), an experienced epigenetics company, and UTHealth. UTHealth holds the patents containing the claims for the use of Xe-containing liposomes for prevention and treatment of stroke. From a commercialization standpoint, Xe- liposome is an attractive therapeutic candidate due to its low side effects and markedly high BBB diffusion. The goals of this proposal are to optimize the Xe-liposomal administration protocol for long-term cytoprotection, and to find the best epigenetic markers that directly correlate Xe treatment to long-term cytoprotective effects in stroke treatment. Our aims are: 1) to determine the optimal frequency and duration of Xe-liposomal administration and demonstrate sustained cytoprotection by repetitive Xe-liposomal administrations for ischemic stroke treatment; and 2) to determine epigenetic signatures to indicate Xe-sustained cytoprotection. Our long-term goals (STTR Phase II and beyond) are to develop an optimal Xe-liposomal delivery strategy using essential epigenetic markers to demonstrate acute and long-term neuroprotection following stroke, and to translate this technology into a clinical product with sustained stroke stabilization effects.

项目总结/摘要 中风损伤是一个过程，发生在一个长期的病理变化，导致长期的 神经功能障碍对于中风，存在对能够提供安全且有效的治疗的策略的重要需求。 有效稳定低灌注脑，并启动持久的内源性神经保护， 预防长期神经功能障碍。有足够的证据表明，氙（Xe），一种生物活性气体， 具有深刻的神经保护作用，具有快速扩散穿过血脑屏障（BBB）的优点， 最小的副作用在最近的新研究中，德克萨斯大学健康科学中心的研究人员在 Houston（UTHealth）将Xe掺入脂质体中，并证明中风后Xe-脂质体治疗 导致缺血性中风和蛛网膜下腔出血后内源性脑保护的激活。 经证实的细胞保护机制包括内源性细胞保护分子的激活。 Xe-脂质体的重复施用随时间延长了保护作用。虽然详细 重复给药诱导的长期保护机制仍不清楚， 证据支持这种适应性表型是表观遗传介导的。作为表观遗传后处理 与刺激的强度、频率和持续时间高度相关，我们假设重复性间歇性刺激- 以最佳频率和持续时间施用脂质体可以诱导表观遗传后调节， 长期影响。这一假设导致了Zymo研究公司（Zymo）， 经验丰富的表观遗传学公司和UT Health。UTHealth拥有包含使用权利要求的专利 用于预防和治疗中风的含Xe脂质体。从商业化的角度来看， 脂质体由于其低副作用和显著高的BBB扩散而成为有吸引力的治疗候选物。的 该建议的目的是优化Xe-脂质体给药方案以实现长期细胞保护， 为了找到最佳的表观遗传标记，直接相关的长期细胞保护作用， 中风治疗 我们的目的是：1）确定Xe-脂质体给药的最佳频率和持续时间， 通过重复给予Xe-脂质体治疗缺血性中风证明持续的细胞保护作用; 和2）确定表观遗传标记以指示Xe-维持的细胞保护。 我们的长期目标（STTR II期及以后）是开发一种最佳的Xe-脂质体递送策略， 证明中风后急性和长期神经保护的重要表观遗传标记， 将该技术转化为具有持续中风稳定效果的临床产品。