PREDICTIVE GENES, MECHANISMS, AND CLINICAL BIOMARKERS OF SUDEP

描述（由申请人提供）：不明原因的心脏和呼吸节律性崩溃是SUDEP的最终常见机制，是癫痫患者的主要和可预防的死亡原因。最近的证据表明，在脑、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，以及在癫痫发作周围这些通路中功能障碍的临床测量，是SUDEP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，从实验室到床边的转化研究项目来识别、验证和临床评估预测性生物标志物和SUDEP的预防性治疗。SUDEP中心研究管道将由中心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）将扩展来自3个中心（EMU， Dravet综合征诊所，SUDEP DNA库）和其他国家网络的患者DNA样本库，这些样本将使用芯片微阵列分析bbb247优先离子通道和受体基因介导心律失常，呼吸抑制和癫痫。项目2-4 （Baylor U. Michigan， U. Iowa）在SUDEP小鼠模型和来自Dravet综合征病例的诱导多能干细胞的细胞和体内水平上分析这些和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/芝加哥儿童纪念医院）将对Dravet综合征患者和其他猝死高危人群（急性低氧血症、心律失常）癫痫监测期间获得的临床呼吸和心脏生物标志物进行细化。一旦验证，来自这些病例的基因将被添加到贝勒正在开发的增量诊断芯片中，用于临床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。

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.