PREDICTIVE GENES, MECHANISMS, AND CLINICAL BIOMARKERS OF SUDEP

描述（由申请人提供）：无法解释的心脏和呼吸节律崩溃是 SUDEP 的最终常见机制，SUDEP 是癫痫患者主要且可预防的死亡原因。最近的证据表明，在大脑、自主神经、心脏和呼吸通路中共同表达的功能失调的离子通道和受体，以及癫痫发作时这些通路中功能紊乱的临床测量，代表了 SUDEP 的可检测和潜在可治疗的危险因素。该提案描述了一个综合的多中心和多学科合作项目，该项目将结合基础科学、人类神经遗传学和临床生理学方法来研究这些生物风险因素，从实验室到临床转化研究计划，以识别、验证和临床评估 SUDEP 的预测生物标志物和预防性治疗。 SUDEP 中心研究管道将由该中心 6 名研究人员之间的一系列相互关联的工作流程组成。项目 1（贝勒）将扩大 3 个中心（EMU、Dravet 综合征诊所、SUDEP DNA 存储库）和其他国家网络的患者 DNA 样本存储库，将使用芯片微阵列对超过 247 个介导心律失常、呼吸抑制和癫痫的优先离子通道和受体基因进行分析。项目 2-4（贝勒大学密歇根分校、爱荷华大学）在 SUDEP 小鼠模型和来自 Dravet 综合征病例的诱导多能干细胞中，在细胞和体内水平分析这些及相关基因突变的生物学、生理学和药理学，以了解和验证 SUDEP 表型。项目 5（加州大学戴维斯分校/芝加哥儿童纪念馆）将完善在对 Dravet 综合征患者和其他猝死高危人群（发作性低氧血症、心律失常）患者进行癫痫监测时获得的临床呼吸和心脏生物标志物。一旦经过验证，这些病例的基因就会被添加到贝勒正在开发的增量诊断芯片中，用于在诊所对具有其他临床生物标志物的个体进行常规患者风险评估。 公共卫生相关性：癫痫猝死 (SUDEP) 是特发性癫痫过早死亡的主要原因。预防 SUDEP 取决于识别癫痫患者的生物学预测危险因素并利用它们进行适当的治疗干预。该计划的目标是验证综合遗传/临床 SUDEP 风险概况，以筛查和治疗癫痫患者。 免责声明：请注意，以下评论是由审稿人在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。 虽然审稿人有机会根据小组的讨论更新或修改他们的书面评估，但不能保证个人批评在会议讨论后得到更新。 因此，评论可能无法完全反映小组讨论结束时个别审稿人的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是审稿人在会议上实际认为关键的内容的最终决定。

DESCRIPTION (provided by applicant): Unexplained collapse of cardiac and respiratory rhythmicity is a final common mechanism for SUDEP, a major and preventable cause of death in persons with epilepsy. Recent evidence shows that dysfunctional ion channels and receptors co-expressed in brain, autonomic, heart, and respiratory pathways, along with clinical measures of functional disturbances in these pathways at times surrounding seizures represent detectable and potentially treatable risk factors for SUDEP. This proposal describes an integrated multicenter and multidisciplinary collaborative project that will combine a basic science, human neurogenetics, and clinical physiology approaches to these biological risk factors in a bench to bedside translational research program to identify, validate, and clinically evaluate predictive biomarkers and preventative treatments for SUDEP. The SUDEP Center Research Pipeline will consist of a serially interrelated work flow among 6 investigators in the center. Project 1 (Baylor) will expand the repository of DNA samples from patient at 3 centers (EMU, Dravet Syndrome Clinic, SUDEP DNA Repository) and other national networks which will be analyzed using chip microarrays for >247 prioritized ion channel and receptor genes mediating cardiac arrhythmias, respiratory depression and epilepsy. Projects 2-4 (Baylor U. Michigan, U. Iowa) analyze the biology, physiology, and pharmacology of these and related gene mutations at the cellular and in vivo level in SUDEP mouse models and induced pluripotent stem cells from Dravet Syndrome cases in order to understand and validate the SUDEP phenotypes. Project 5 (U.C. Davis/Childrens Memorial Chicago) will refine clinical respiratory and cardiac biomarkers obtained during epilepsy monitoring of individuals with Dravet Syndrome and others at high risk of sudden death (ictal hypoxemia, cardiac arrhythmia). Once validated, genes from these cases are added to an incremental diagnostic chip in development at Baylor for routine patient risk assessment in clinics in individuals with other clinical biomarkers. PUBLIC HEALTH RELEVANCE: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in idiopathic epilepsy. Preventing SUDEP depends upon identifying biologically predictive risk factors in individuals with epilepsy and using them to mak appropriate therapeutic interventions. The goal of this program is to validate a combined genetic/clinical SUDEP risk profile to screen and treat individuals with epilepsy. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.