Targeting distinct DNA methylation signatures in pediatric glioma using HITMA

使用 HITMA 靶向儿童神经胶质瘤的独特 DNA 甲基化特征

• 批准号: 10558991
• 负责人: MICHAEL ROUNTREE
• 金额: $ 35.5万
• 依托单位: NZUMBE EPIGENETICS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2023-01-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558991
• 关键词: Aberrant DNA Methylation; Apoptosis; Cells; Childhood Glioma; DNA Methylation; Disease; Goals; Mediating; Methylation; Neurons; Patients; Phenotype; Repetitive Sequence; Survival Rate; Testing; Therapeutic; Validation; base; cell type; combat; design; innovation; transcription activator-like effector nucleases

Pediatric high-grade gliomas (pHGG) have proven to be extremely difficult to treat with a dismal survival rate. Fresh, innovative therapeutic approaches are desperately needed to combat this devastating disease. Hypomethylated Induced Target Mediated Apoptosis (HITMA), is a therapeutic strategy that targets and induces apoptosis only in cells that show an aberrant DNA methylation phenotype at repetitive sequences. Aberrant global DNA methylation is a hallmark of some pHGGs; however, the methylation status of repetitive sequences hasn’t been carefully evaluated. The first goal of this proposal is to thoroughly evaluate the methylation status of repetitive elements in different pHGG subtypes. Based on this, the second goal is to identify and generate an optimal HITMA strategy that will attack select subclasses of pHGG while sparing normal neural cell types. Therefore, if our HITMA-based strategy in pHGG is successful, we expect it to transform patient-specific therapeutic strategies in pHGG.

小儿高级别胶质瘤（pHGG）已被证明是非常困难的治疗与令人沮丧的生存率。迫切需要新的、创新的治疗方法来对抗这种毁灭性的疾病。低甲基化诱导的靶介导的细胞凋亡（HITMA）是一种治疗策略，其仅在重复序列处显示异常DNA甲基化表型的细胞中靶向并诱导细胞凋亡。异常的整体DNA甲基化是一些pHGG的标志;然而，重复序列的甲基化状态尚未得到仔细评估。该提案的第一个目标是彻底评估不同pHGG亚型中重复元件的甲基化状态。在此基础上，第二个目标是识别和生成最佳HITMA策略，该策略将攻击pHGG的选定子类，同时保留正常的神经细胞类型。因此，如果我们在pHGG中基于HITMA的策略是成功的，我们希望它能改变pHGG中的患者特异性治疗策略。