MOUSE MODELS FOR EXPLORING THE DEVELOPMENTAL ORIGINS OF SEX DIFFERENCES IN GLIOBLASTOMA

用于探索胶质母细胞瘤性别差异发育起源的小鼠模型

• 批准号: 9163931
• 负责人: Joshua B Rubin
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9163931
• 关键词: Accounting; Acute; Acute Lymphocytic Leukemia; Address; Affect; Age; Alleles; Astrocytes; Biological Models; Biology; Cancer Biology; Cells; Clinical; Clinical Research; Communities; Development; Disease; Elements; Epidermal Growth Factor Receptor; Epigenetic Process; Estrogens; Event; Exhibits; Female; Gene Dosage; Genes; Genotype; Geographic Locations; Glioblastoma; Gliomagenesis; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Growth; Health; Hormonal; Hormones; Human; Incidence; Individuality; Malignant - descriptor; Malignant Neoplasms; Measures; Mesenchymal; Modeling; Molecular; Mus; Neurofibromatosis Type 1 Protein; Oncogenic; Outcome; Ovary; Pathway interactions; Patients; Pattern; Phenotype; Ploidies; Positioning Attribute; Predisposition; Process; Publishing; Research; Resistance; Response Elements; Sex Characteristics; Sex Chromosomes; Signal Pathway; TP53 gene; Testing; Testis; Testosterone; Translational Research; X Chromosome; Y Chromosome; abstracting; authority; autosome; base; cancer therapy; cell transformation; chemotherapy; experience; genome-wide; in utero; in vitro activity; in vivo; innovation; insight; male; meningioma; mouse model; new therapeutic target; novel; novel strategies; personalized approach; precision medicine; response; sex; sexual dimorphism; success; therapeutic target; treatment response; tumorigenesis; tumorigenic

Abstract Despite decades of research, curing glioblastoma (GBM) remains an intractable problem. Fresh approaches are needed and in this proposal we will use sex differences in GBM to generate novel insights into mechanisms that control gliomagenesis and treatment responses. Like many other cancers, GBM occurs more frequently in males than females, regardless of age or geographical location. The reason(s) for sex differences in cancer incidence and survival are largely unknown but must be traceable to the actions of sex chromosomes, and the long-term epigenetic and acute effects of sex hormones. Understanding how sex imparts affects cancer incidence and outcome will be essential for development of truly personalized precision medicine approaches to cancer treatment, as accounting for patient sex is a fundamental component of their individuality. In this proposal we will use sex differences to create a parallax-like effect, in which previously unapparent elements of GBM biology will be revealed. We recently used this approach and discovered cell intrinsic sex differences exist in thresholds for malignant transformation in a model of mesenchymal GBM. We hypothesize that fundamental mechanisms of cancer susceptibility and resistance lie within the biology of sex differences. To complete these studies we will build a new model system to examine sex differences in GBM. We have two specific aims. In the first aim we will adapt our model of mesenchymal GBM to support the analysis of how early events in sexual differentiation pattern responses to oncogenic events and establish different thresholds for transformation in male and female astrocytes. We will make use of the four- core genotypes model of sex differences and address hypotheses regarding how differences in sex chromosome complement and the epigenetic effects of sex hormones affect tumorigenesis. In the second aim we will use the same model to address the critical translational science objective of determining which of these developmental factors underlies sex differences in response to common and experimental chemotherapeutics. Together these studies constitute a pioneering approach to GBM biology. Success in these studies has real potential for novel insights with substantial translational significance as we strive to implement personalized precision approaches to treatment for GBM and other cancers.

抽象的 尽管经过数十年的研究，治疗胶质母细胞瘤（GBM）仍然是一个棘手的问题。新方法 需要，在本提案中，我们将利用 GBM 中的性别差异来产生新的见解 控制神经胶质瘤发生和治疗反应的机制。与许多其他癌症一样，GBM 的发生率更高 无论年龄或地理位置如何，男性多于女性。性别差异的原因 癌症的发病率和生存率在很大程度上是未知的，但必须追溯到性行为 染色体，以及性激素的长期表观遗传和急性影响。了解性爱的方式 影响癌症发病率和结果对于发展真正个性化的精准度至关重要 癌症治疗的医学方法，因为考虑患者性别是其基本组成部分 个性。在这个提案中，我们将利用性别差异来创建类似视差的效果，其中之前 GBM 生物学中不明显的元素将被揭示。我们最近使用了这种方法并发现了细胞 在间充质 GBM 模型中，恶性转化阈值存在内在性别差异。我们 假设癌症易感性和耐药性的基本机制在于 性别差异的生物学。为了完成这些研究，我们将建立一个新的模型系统来检查性别 GBM 的差异。我们有两个具体目标。第一个目标是调整我们的间充质 GBM 模型 支持分析性分化模式中的早期事件如何响应致癌事件和 建立男性和女性星形胶质细胞转化的不同阈值。我们将利用四个—— 性别差异的核心基因型模型，并提出关于性别差异如何产生的假设 染色体补体和性激素的表观遗传效应影响肿瘤发生。在第二个目标中 我们将使用相同的模型来解决关键的转化科学目标，即确定其中哪些 发育因素是对常见和实验化疗药物反应的性别差异的基础。 这些研究共同构成了 GBM 生物学的开创性方法。这些研究的成功具有现实意义 当我们努力实现个性化时，具有重大转化意义的新颖见解的潜力 GBM 和其他癌症的精准治疗方法。