Abnormal Interleukin 1-B Inflammasome Activation and Epilpesy Surgery Outcomes

项目概要： 颞叶癫痫手术后癫痫复发率为50%，颞叶外癫痫手术后癫痫复发率为60%-70 癫痫手术独家专注于提炼“癫痫定位”尚未大幅改善癫痫发作 成果。我们最近提出，遗传易感患者的新发癫痫可能会影响 “晚期”复发首先表现为术后数月至数年无复发。证据越来越多 神经炎症在癫痫中的作用，白细胞介素-1 β（IL-1β）表达的遗传变异与 人类创伤后癫痫的风险我们将探讨中心假设，即IL-1基因的遗传变异性， 1β及其相关炎性小体转化为癫痫后小胶质细胞活化模式的改变 手术，促进切除边缘脑组织中随后的癫痫发生， 癫痫复发首次癫痫发作复发的时间是我们的主要结局。术后6个月峰值 我们的次要结果是在此之前无癫痫患者的EEG。 在特定目标1中，我们回顾性地探讨了癫痫发作结果与遗传变异性之间的关系。 IL-1β和相关炎性小体激活在切除的癫痫脑组织中的作用。我们专注于SA 1a）-SNP） rs 1143634 IL-1β基因变体;和SA 1b）-控制IL-1 β合成的多蛋白复合物的激活 1β [核苷酸结合和寡聚化结构域样受体家族， 3（NLRP 3）炎性体]，如通过炎性体组分的RNA/蛋白质提取及其 免疫组化定位于小胶质细胞。在特定目标2中，我们探讨了MRI与 使用脑MRI进行围手术期神经炎症和术后癫痫发生的特征， 坎皮纳斯大学24-72小时后手术。在具体目标3中，我们扩展了SA 1的问题， 2使用从马约诊所和克利夫兰诊所入组的25例患者的前瞻性队列（SA 3a） 确定围手术期血清IL-1β、MMP-9或IL-18的测量值是否与原发性 次要结局，并确定在未来确定性项目中研究的理想采集时间;（SA 3b）研究 我们提出的术后癫痫发生生物标志物的开发时间表;和（SA 3c）探索我们的 通过研究小胶质细胞的相对（边缘与切除的癫痫组织的核心）程度， 活化，IL-1β组织表达，结果有利vs不利。 我们强有力的初步数据支持我们的假设。多个研究中心（克利夫兰诊所，马约 诊所和坎皮纳斯大学）将间接测试可行性，并建立未来所需的基础设施 权威研究我们充分利用现有的资源，并在以下方面建立了富有成效的合作记录 我们的研究者将优化研究实施的效率并确保研究完成。如果成功，这项工作 将为癫痫手术后手术结果的创新研究打开大门， 鉴于市场上有多种选择性IL-1β调节剂，

Project Summary: Seizures recur in 50% of patients after temporal lobe epilepsy surgery and in 60%-70% after extra-temporal lobe epilepsy surgery. An exclusive focus on refining “epilepsy localization” has not yet drastically improved seizure outcomes. We recently proposed that de-novo epileptogenesis in genetically predisposed patients may influence “late” recurrences first manifesting after months to years of postoperative seizure-freedom. Evidence is accruing on neuro-inflammation's role in epilepsy, and genetic variation in Interleukin-1β (IL-1β) expression was linked to the risk of posttraumatic human epilepsy. We will explore the central hypothesis that genetic variability in IL- 1β and its related inflammasome translates into an altered pattern of microglial activation after epilepsy surgery, facilitating subsequent epileptogenesis in brain tissue at the edge of the resection and later seizure recurrence. Time to first seizure recurrence is our primary outcome. Spikes on 6-month postoperative EEG in patients who were seizure-free up to that point is our secondary outcome. In Specific Aim 1, we retrospectively explore the relationship between seizure outcomes and genetic variability in IL-1β and related inflammasome activation in resected epileptic brain tissue. We focus on SA1a)- the SNP) rs1143634 IL-1β gene variant ; and SA1b)- activation of the multi-protein complex controlling the synthesis of IL- 1β [the nucleotide binding and oligomerization domain like receptor family pyrin domain-containing 3(NLRP3)inflammasome], as measured by RNA/protein extraction of inflammasome components and their immunohistochemical localization to microglia. In Specific Aim 2, we explore the relationship between MRI signatures of peri-operative neuroinflammation and postoperative epileptogenesis using brain MRI done in the University of Campinas 24-72 hours after surgery. In Specific Aim 3, we expand the questions of SA1 and 2 using a prospective cohort of 25 patients enrolled from Mayo Clinic and Cleveland Clinic as we (SA3a) determine if peri-operative serum measurements of IL-1β, MMP-9, or IL-18 correlate with the primary and secondary outcome, and identify the ideal collection time to study in a future definitive project; (SA3b) study the timeframe for development of our proposed postoperative epileptogenesis biomarkers; and (SA3c) explore our proposed mechanism by studying the relative (margin vs.core of resected epileptic tissue) degree of microglial activation, IL-1β tissue expression in those with favorable vs unfavorable outcomes. Our strong preliminary data support our hypothesis. The collaboration of multiple sites (Cleveland Clinic, Mayo Clinic, and University of Campinas) will indirectly test the feasibility and build infrastructure needed for a future definitive study. We take advantage of existing resources and a track record of productive collaborations among our investigators to optimize the efficiency of study conduct and ensure study completion. If successful, this work will open the door for an innovative line of research on surgical outcomes after epilepsy surgery with a significant potential for altering clinical care given the multitude of selective IL-1β modifiers on the market.