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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结