Project 1: Sex-specific developmental epigenetics in gliomagenesis

项目 1：神经胶质瘤发生中的性别特异性发育表观遗传学

• 批准号: 10023714
• 负责人: Joshua B Rubin
• 金额: $ 37.47万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023714
• 关键词: Acute; Address; Adult; American; Biological; Biology; Cancer Model; Cell Communication; Cell Cycle; Cell Cycle Regulation; Cells; Child; Chromatin; Chromatin Structure; Clinic; Clinical Trials Design; Coupled; Data; Development; Disease; Electroporation; Enhancers; Epigenetic Process; Exhibits; Female; Fertilization; Foundations; Four Core Genotypes; Gene Expression; Gene Expression Profile; Genes; Genetic; Glioblastoma; Glioma; Gliomagenesis; Goals; Gonadal Steroid Hormones; Guide RNA; Hormones; In Vitro; Incidence; Integrin Signaling Pathway; Integrins; Laboratories; Lead; Life; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Microglia; Mitotic Checkpoint; Modeling; Molecular; Natural Products; Oncogenes; Other Genetics; Outcome; Pathway interactions; Patient imaging; Patients; Pattern; Phenotype; Ploidies; Positioning Attribute; Predisposition; Publications; Publishing; Regulatory Pathway; Sex Chromosomes; Sex Differences; Signal Transduction; Study models; TP53 gene; Testing; Time; Tissues; Tumor Suppressor Proteins; Work; base; chemotherapy; defined contribution; health difference; improved; improved outcome; in utero; innovation; insight; iron metabolism; macrophage; male; meetings; metaplastic cell transformation; mouse model; multi-scale modeling; neoplastic cell; novel; nuclease; response; sex; sexual dimorphism; standard care; success; synergism; therapeutic target; tool; transcriptome; treatment response; tumorigenesis

PROJECT SUMMARY Glioblastoma (GBM) is the most devastating form of brain cancer. In the next year, approximately 22,000 Americans will develop GBM and nearly the same number will die from it. While GBM occurs in both males and females, we can reliably predict that of the 22,000 new cases, 8,500 will be in females while the remaining 13,500 cases will be in males. Moreover, while the median survival for female GBM patients next year is expected to be approximately 22 months, for males it will be closer to 16 months. The molecular bases for these consistent and significant sex differences in incidence and survival are unexplained. In the absence of an explanation, it is impossible to fully know what the implications are for modeling GBM in the laboratory and for treating GBM in the clinic. Defining the genetic and epigenetic mechanisms that underlie sex differences in GBM incidence and survival is the focus of this project. We recently published an analysis of GBM patient imaging, transcriptomes, and survival in which we determined that female GBM patients exhibit greater response to the current standard treatments and that their survival is highly correlated with expression of components of the integrin signaling pathway. In contrast, male GBM patients exhibit less robust response to current treatment and their survival appears to be more potently determined by expression levels of the cell cycle regulatory machinery. These data not only provide new insights into sex differences in GBM biology, they suggest that sex-specific targeting of pathways that support survival in females and males could lead to improved outcomes for all patients. Sex differences in health and disease accrue throughout life as a consequence of sexual differentiation. Sexual differentiation, which begins at the time of fertilization, involves genetic and epigenetic mechanisms, as well as the acute actions of circulating sex hormones. We have developed murine models for studying sex differences in GBM. Here, we will use our innovative Cas-9 adaptation of the established four-core genotypes model for measuring the distinct contributions of sex chromosome complement and gonadal secretions to sex differences in GBM biology. Coupled with in utero electroporation of gRNAs and other genetic constructs, we will be uniquely positioned to assess how sex-specific changes in chromatin structure and expression of specific genes mediate the sex differences in GBM. We have two aims to address the hypothesis that sex differences in GBM incidence and outcome are determined at early stages of in utero sexual differentiation (Aim 1) and involve sex-specific patterning in gene expression and activity in integrin and cell cycle regulatory pathways (Aim 2). At all stages of this work we will incorporate specific questions about sexual differentiation and iron metabolism (Project 2) and microglia function (Project 3). Together these studies will provide critical information in our effort to understand the molecular basis for sex differences in GBM and a path for the implementation of sex-specific treatment for GBM and other cancers that exhibit sex differences in incidence and outcome.

项目概要 胶质母细胞瘤（GBM）是最具破坏性的脑癌。明年，大约有 22,000 美国人将会患上 GBM，并且几乎同样数量的人会因此而死亡。虽然 GBM 发生在男性和女性中 女性，我们可以可靠地预测，在 22,000 例新病例中，8,500 例为女性，其余 13,500 例为女性 病例多为男性。此外，虽然明年女性 GBM 患者的中位生存期预计为 大约22个月，男性则接近16个月。这些一致且一致的分子基础 发病率和生存率的显着性别差异尚无法解释。在没有解释的情况下，这是 不可能完全了解实验室建模 GBM 和治疗 GBM 的影响。 诊所。定义 GBM 性别差异背后的遗传和表观遗传机制 发病率和生存率是该项目的重点。我们最近发表了 GBM 患者影像学分析， 转录组和生存率，我们确定女性 GBM 患者对 目前的标准治疗方法，其存活率与这些成分的表达高度相关 整合素信号通路。相比之下，男性 GBM 患者对当前治疗的反应不太强烈，并且 它们的生存似乎更有效地由细胞周期调节机制的表达水平决定。 这些数据不仅为 GBM 生物学中的性别差异提供了新的见解，还表明性别特异性 针对支持女性和男性生存的途径可以改善所有患者的预后。 由于性别差异，健康和疾病方面的性别差异在一生中不断累积。性 分化从受精时开始，涉及遗传和表观遗传机制，以及 循环性激素的急性作用。我们开发了用于研究性别差异的小鼠模型 在GBM中。在这里，我们将使用我们对已建立的四核基因型模型的创新 Cas-9 改编 测量性染色体补体和性腺分泌对性别差异的独特贡献 在 GBM 生物学中。结合 gRNA 和其他基因构建体的子宫内电穿孔，我们将拥有独特的优势 旨在评估染色质结构和特定基因表达的性别特异性变化如何介导 GBM 的性别差异。我们有两个目标来解决 GBM 发病率存在性别差异的假设 和结果在子宫内性别分化的早期阶段确定（目标 1），并涉及性别特异性 整合素和细胞周期调控途径的基因表达和活性模式（目标 2）。在各个阶段 这项工作我们将纳入有关性别分化和铁代谢的具体问题（项目 2）和 小胶质细胞功能（项目 3）。这些研究将共同​​提供关键信息，帮助我们理解 GBM性别差异的分子基础以及实施性别特异性治疗的路径 GBM 和其他癌症在发病率和结果方面表现出性别差异。