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Hypoxia Regulates Notch Turnover in Glioma Stem Cells Through Vasorin

缺氧通过血管素调节胶质瘤干细胞的缺口转换

基本信息

批准号：
9752672
负责人：
Jennifer S Yu
金额：
$ 34.67万
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：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752672
关键词：
Adaptor Signaling Protein Adult Animals Apoptosis Area Back Binding Brain CASP3 gene Cell Nucleus Cell membrane Cells Cleaved cell Clinical Data Development Early Endosome Embryo Endocytosis Endosomes Family member Gene Expression Genes Glioblastoma Glioma HIF1A gene Hypoxia Immunofluorescence Immunologic Impairment In Situ Nick-End Labeling In Vitro Ligand Binding Ligands Lysosomes Malignant - descriptor Mediating Modeling Numbness Pathogenesis Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phenotype Primary Brain Neoplasms Process Prognostic Factor Prognostic Marker Proliferation Marker Property Proteins Proteolytic Processing Quantitative Reverse Transcriptase PCR Radiation Recycling Regulation Resistance Response Elements Role STAT3 gene Signal Transduction Stem cells Testing Toxic effect Transactivation Western Blotting Xenograft procedure base cancer stem cell chemotherapy conventional therapy gamma secretase hypoxia inducible factor 1 improved in vivo inhibitor/antagonist knock-down late endosome mouse model notch protein novel novel therapeutics outcome forecast overexpression preclinical study programs public health relevance receptor response secretase self-renewal side effect small hairpin RNA stemness therapeutic target therapy resistant trafficking tumor tumor growth tumor hypoxia tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cancer stem cells reside in hypoxic areas and contribute to tumor progression. These cells are particularly difficult to treat because they are inherently resistant to conventional therapy, and their microenvironment reduces the efficacy of radiation and impairs delivery of chemotherapy. Glioblastoma is an incurable primary brain tumor that is characterized by regions of hypoxia. Notch signaling maintains GSCs within the hypoxic niche, but how Notch is dysregulated is unclear. Our preliminary data strongly suggest that hypoxia can regulate membranous Notch levels, thereby regulating receptor availability for ligand binding. We have found that the recently identified hypoxia-regulated protein, Vasorin, is preferentially expressed in GSCs to regulate Notch signaling. Our data suggest that Vasorin regulates GSC self-renewal by inhibiting the lysosomal degradation of Notch1. Thus, we have identified a novel mechanism by which hypoxia directs Notch signaling: regulation of receptor turnover. Our central hypothesis is that Vasorin regulates GSC self-renewal within the hypoxic niche by regulating Notch signaling and that targeting Vasorin may improve GBM therapy. We will test our hypothesis through mechanistic and preclinical studies. In Aim 1, we will determine the role of Vasorin in mediating GSC properties and tumorigenic potential in vitro and in vivo. In Aim 2, we will define the role of Vasorin in regulating Notch signaling to promote GSC self-renewal under hypoxic conditions. In Aim 3, we will assess Vasorin as a prognostic biomarker and provide proof-of-principle that maximizing Notch inhibition by dual targeting of Vasorin and Notch proteolytic processing can improve survival in mouse models of glioblastoma. Importantly, Vasorin does not appear to be expressed in normal embryonic or adult brain. Therefore, targeting Vasorin may have limited normal brain toxicity. These data will reveal an important role for Vasorin in regulating Notch signaling and have significant clinical ramifications. Current therapies using hypoxia modifiers or Notch pathway inhibitors, such as -secretase inhibitors, are limited by side effects. If successful, the findings of this study will provide a strong rationale for the development of novel therapeutics against Vasorin.

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Introduction to laser thermal therapy for brain disorders.

DOI：
10.1080/02656736.2020.1789764
发表时间：
2020-07
期刊：
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
影响因子：
0
作者：
Yu JS;Mohammadi AM
通讯作者：
Mohammadi AM

Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-Like Cells.

DOI：
10.3390/biomedicines6020042
发表时间：
2018-04-08
期刊：
Biomedicines
影响因子：
4.7
作者：
Hao J;Yu JS
通讯作者：
Yu JS

Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression.

DOI：
10.1016/j.celrep.2020.108522
发表时间：
2021-01-05
期刊：
Cell reports
影响因子：
8.8
作者：
Huang H;Yu X;Han X;Hao J;Zhao J;Bebek G;Bao S;Prayson RA;Khalil AM;Jankowsky E;Yu JS
通讯作者：
Yu JS

The effects of extra high dose rate irradiation on glioma stem-like cells.