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Understanding Sex Disparities in Gliomas Through Sex Differences in Mitochondrial Activity

通过线粒体活动的性别差异了解神经胶质瘤的性别差异

基本信息

批准号：
9815248
负责人：
Joseph Edward Ippolito
金额：
$ 17.08万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-13 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9815248
关键词：
Address Adult Affect Age Amino Acids Animal Model Animals Astrocytes Automobile Driving Biological Assay Biomass Brain Neoplasms Cancer Patient Cell Proliferation Cells Central obesity Child Citric Acid Cycle Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Complex Consumption DNA polymerase gamma Development Diet Disease Dominant-Negative Mutation Embryo Engineering Epigenetic Process Female Fertilization Gene Expression Glioblastoma Glioma Glucose Glutamine Glycolysis Goals Gonadal Steroid Hormones Growth Health Heterogeneity High Fat Diet Image Incidence Individual Knock-out Laboratories Life Link Long-Term Effects Magnetic Resonance Imaging Malignant Neoplasms Menopausal Status Metabolic Metabolism Mitochondria Mitochondrial Inheritance Modeling Modification Mus NF1 gene Nuclear Nutrient Obesity Outcome Patient-Focused Outcomes Patients Pattern Phenotype Play Ploidies Positron-Emission Tomography Principal Investigator Reporting Research Proposals Respiration Role Sex Chromosomes Sex Differences Sex Functioning Source Sugar Acids Testing Tetanus Helper Peptide Tetracyclines Therapeutic Tissue Harvesting Transformed Cell Line Tumor Tissue Tumorigenicity Visceral Woman adenoviral-mediated cancer cell cancer diagnosis cancer health disparity cancer type cell growth fluorodeoxyglucose imaging modality in utero in vivo innovation insight male malignant phenotype men metabolic phenotype mitochondrial dysfunction mitochondrial metabolism mortality mouse model novel nutrient metabolism nutrition obesogenic oncology outcome forecast patient stratification programs sex sex disparity therapy resistant tumor tumor growth tumor metabolism tumorigenesis uptake

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Ippolito, Joseph Edward PROJECT SUMMARY There is a sex disparity seen in cancers throughout the body where males have both a higher incidence and a higher mortality than females. This is not only true for adults, but is also seen in children as well, suggesting that factors other than the effects of sex hormones may be playing a role in this phenomenon. This is especially true for glioblastomas (GBM) that comprise over 50% of brain tumors and are characterized by resistance to therapies and a dismal prognosis (median survival - 15 months). Because enhanced nutrient consumption and metabolism are critical to enhanced tumorigenesis and its effect on poor patient outcomes, our group investigates the presence of sex differences in cancer metabolism that may be driving the sex disparities that are observed in many cancers. We have uncovered laboratory and clinical evidence demonstrating that male brain tumors have enhanced nutrient uptake and metabolism (specifically sugars and amino acids) compared to female tumors. We have further identified that the largest sex differences in cancer metabolism come from the mitochondria, the part of the cell that is the critical for generating energy and biosynthetic building blocks for the cell for growth. Because metabolism is not only restricted to the tumor, but involves the entire patient, we have investigated the effects of sex differences in nutrition and obesity in cancer patient survival. We have discovered that women with “male-pattern” increased visceral abdominal obesity selectively do much worse compared to all other patients in multiple cancers. These findings suggest that the sex differences that we see in cancers may not only be related to tumor mitochondria, but nutrition and its overall metabolic health of the individual. In this proposal, we will develop new animal models to test the hypothesis that sex differences in mitochondrial activity underlie sex differences in tumor development. Our long term goal is to understand the metabolic basis of sex disparities in cancer patients through a combination of tumor and host metabolism. In the first aim of this proposal, we will use an established model (Nf1-/-/DNp53) for sex differences in GBM and deplete mitochondria in the cancer cells to test for sex differences in cancer cell phenotype and metabolism. In the second aim, we will determine the effects of obesogenic diets on sex differences in brain tumor mitochondrial activity and growth. This research proposal is innovative because it opens up a new paradigm in the oncology field that investigates sex-specific differences in cancer and host metabolism. This proposal will generate new insights into the mechanism behind sex differences in mitochondrial activity and the impact of nutrition on sex differences in the malignant phenotype. We are beginning to develop a platform for novel readily-translatable imaging methods and therapeutic approaches that treat not only brain tumors, but multiple malignancies. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

项目主管/首席研究员（最后、第一、中）：伊波利托，约瑟夫·爱德华