Molecular basis for the impact of sex on brain tumorigenesis

性别对脑肿瘤发生影响的分子基础

• 批准号: 10212288
• 负责人: Joshua B Rubin
• 金额: $ 37.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212288
• 关键词: Address; Affect; American; Astrocytes; Biological; Biological Models; Bone Marrow; Brain; Brain Neoplasms; Cell Aging; Cell model; Cells; Clinic; Clinical Research; DNA Damage; Epigenetic Process; Etoposide; Evaluation; Exhibits; FRAP1 gene; Female; Fibroblasts; Funding; Gene Expression Profile; Genomics; Glioblastoma; Goals; Growth Factor; Human; Hydrogen Peroxide; In Vitro; Incidence; Inflammatory; Investigation; Knowledge; Laboratories; Malignant Neoplasms; Modeling; Molecular; Mus; Neurodegenerative Disorders; Pathologic; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Ploidies; Property; Publishing; Radiation; Regulation; Reporting; Repressor Proteins; Research; Role; Severities; Sex Chromosomes; Sex Differences; Sex Differentiation; Stromal Cells; TP53 gene; Techniques; Technology; Therapeutic; Translations; Tumor Promotion; anticancer research; base; cancer therapy; chemokine; chemotherapy; cytokine; defined contribution; experience; improved outcome; innovation; insight; male; malignant breast neoplasm; mouse model; neoplastic cell; nervous system disorder; neuroinflammation; novel; novel strategies; prostate cancer model; response; senescence; sex; sex disparity; sexual dimorphism; success; tool; treatment optimization; treatment response; tumor; tumor growth; tumorigenesis; tumorigenic

Abstract In the next year, approximately 22,000 Americans will develop glioblastoma (GBM) and nearly the same number will die from it. Further, 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 between 17 and 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 of sex differences are for modeling GBM in the laboratory and for treating GBM in the clinic. Identifying targetable mechanisms underlying sex differences in survival are the focus of this project, and our goal is to improve outcomes for all GBM patients. Building on our published and preliminary studies supported during the prior funding period of this RO1, we now hypothesize that sex differences in cellular senescence contribute to the sex disparity in glioblastoma (GBM) incidence and survival. As radiation or chemotherapy induced senescence is a mechanism of stopping tumor growth, we will focus on the mechanisms that endow female cells with greater ability to undergo senescence than their male counterparts in response to DNA damage. While cellular senescence has been extensively studied in normal and pathological states, studies in cancer have focused almost exclusively on fibroblast and bone marrow stromal cell senescence in breast and prostate cancer models. There has been little to no investigation of the role that cellular senescence plays in brain tumor promotion or treatment response, or any focus on sex differences in cellular senescence. We have two Specific Aims in which we will build on our prior success and utilize the extensively validated model systems for studying sex differences in GBM that we developed. We will apply innovative genomic technologies to define the contributions of sex differences in p21 and Rb functions to the induction of senescence, and will determine whether Brd4 and sex-specific epigenetics are required for sex differences in astrocyte and GBM cell senescence and the senescence-associated secretory phenotype.

抽象的 明年，大约 22,000 名美国人将患上胶质母细胞瘤 (GBM)，并且数量几乎相同 将会死于它。此外，我们可以可靠地预测，在 22,000 例新病例中，8,500 例为女性，而 其余 13,500 例为男性。此外，虽然明年女性 GBM 患者的中位生存期 预计年龄在 17 至 22 个月之间，男性则接近 16 个月。的分子基础 这些在发病率和生存率方面一致且显着的性别差异尚无法解释。在没有 解释，不可能完全了解性别差异对 GBM 建模的影响 实验室和临床治疗 GBM。确定性别差异背后的目标机制 生存是该项目的重点，我们的目标是改善所有 GBM 患者的治疗结果。建立在我们的 在本 RO1 的先前资助期间发表和支持的初步研究，我们现在假设 细胞衰老的性别差异导致胶质母细胞瘤（GBM）的性别差异 发病率和生存率。由于放疗或化疗诱导的衰老是阻止肿瘤的机制 生长，我们将重点关注赋予女性细胞更强的衰老能力的机制 对 DNA 损伤的反应优于男性。尽管细胞衰老已被广泛 在正常和病理状态下进行研究，癌症研究几乎完全集中在成纤维细胞和 乳腺癌和前列腺癌模型中的骨髓基质细胞衰老。几乎没有 研究细胞衰老在脑肿瘤促进或治疗反应中所起的作用，或任何 关注细胞衰老的性别差异。我们有两个具体目标，我们将在之前的基础上进一步发展 成功并利用广泛验证的模型系统来研究 GBM 中的性别差异 发达。我们将应用创新的基因组技术来定义 p21 中性别差异的贡献 和 Rb 具有诱导衰老的功能，并将决定 Brd4 和性别特异性表观遗传学是否 是星形胶质细胞和 GBM 细胞衰老以及衰老相关分泌的性别差异所必需的 表型。