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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要在接下来的一年里，大约22,000名美国人将患上胶质母细胞瘤(GBM)，几乎相同数量的人都会因此而死。此外，我们可以可靠地预测，在22,000例新病例中，8,500例将发生在女性，而其余13,500例将发生在男性。此外，虽然明年女性GBM患者的中位存活率预计将在17到22个月之间，而男性将接近16个月。的分子碱基这些在发病率和存活率方面一贯而显著的性别差异是无法解释的。在缺少解释，不可能完全知道性别差异对在实验室和临床上用于治疗基底膜。确定潜在的性别差异的目标机制生存是这个项目的重点，我们的目标是改善所有GBM患者的预后。建立在我们的在此RO1的前一个资助期内支持的已发表和初步研究，我们现在假设细胞衰老的性别差异是胶质母细胞瘤(GBM)性别差异的原因发病率和存活率。由于放化疗引起的衰老是阻止肿瘤的一种机制生长，我们将专注于赋予女性细胞更强的衰老能力的机制比男性同龄人对DNA损伤的反应更好。虽然细胞衰老已经被广泛地在正常和病理状态下进行的研究，对癌症的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骨髓基质细胞的衰老。几乎没有细胞衰老在脑肿瘤促进或治疗反应中的作用的研究关注细胞衰老中的性别差异。我们有两个具体目标，我们将在以前的基础上再接再厉成功地利用我们广泛验证的模型系统来研究GBM的性别差异发展起来的。我们将应用创新的基因组技术来确定性别差异在p21中的作用。和Rb对衰老的诱导作用，并将决定Brd4和性别特异性表观遗传学是星形胶质细胞和基底膜细胞衰老和衰老相关分泌的性别差异所必需的表型。