Epigenetic Markers and Sustained Cytoprotection for Stroke Treatment

项目摘要/摘要 中风损伤是一个长期发生的过程，其病理变化会导致长期的 神经功能障碍。对于中风来说，重要的是需要一种能够提供安全和 有效稳定低灌注脑，启动长效内源性神经保护 预防长期的神经功能障碍。充分的证据表明，氙气(Xe)，一种生物活性气体， 具有深远的神经保护作用，具有快速扩散通过血脑屏障(BBB)的优势 副作用最小。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 休斯顿(UTHealth)将Xe引入脂质体，并证明Xe-脂质体治疗中风后 导致缺血性卒中和蛛网膜下腔出血后内源性脑保护的激活。 已证实的Xe细胞保护机制包括激活内源性细胞保护分子。 重复给药Xe-脂质体可延长保护作用的时间。虽然详细的 重复给药诱导长期保护的潜在机制仍不清楚，正在形成 有证据表明，这种适应性表型是由表观遗传调节的。作为表观遗传后处理 与刺激的效力、频率和持续时间高度相关，我们假设重复的间歇Xe- 以最佳频率和持续时间给药可诱发表观遗传后处理 在长期影响方面。这一假设导致了Zymo研究公司(Zymo)和 经验丰富的表观遗传学公司和UTHealth。UTHealth持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，Xe- 脂质体副作用小，血脑屏障弥散性高，是一种有吸引力的候选治疗药物。这个 这项建议的目标是优化Xe-脂质体的长期细胞保护给药方案，以及 寻找Xe治疗与长期细胞保护作用直接相关的最佳表观遗传标记。 中风治疗。 我们的目标是：1)确定Xe-脂质体给药的最佳频率和持续时间 显示持续的细胞保护通过重复给药Xe-脂质体治疗缺血性卒中； 2)确定表观遗传特征以表明Xe持续的细胞保护作用。 我们的长期目标(STTR第二阶段及以后)是开发一种最佳的Xe脂质体递送策略，使用 必要的表观遗传学标记物，以证明中风后的急性和长期神经保护，并 将这项技术转化为具有持续中风稳定效果的临床产品。

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.