FUNCTIONAL DISSECTION OF THE K27M HISTONE MUTATION IN GLIOMAGENESIS

胶质瘤发生中 K27M 组蛋白突变的功能解剖

基本信息

批准号：
10117195
负责人：
Oren Josh Becher
金额：
$ 17.31万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117195
关键词：
ACVR1 gene Adult Glioma Affect Apoptosis Autopsy Biology Biopsy Bone Morphogenetic Proteins Brain Stem Cell Differentiation process Cells Child Childhood Brain Neoplasm Clinical Trials Complex Dependence Development Diagnosis Diffuse intrinsic pontine glioma Disease Dissection Excision Foundations Future Genes Genetic Genetic Transcription Genetically Engineered Mouse Glioma Gliomagenesis Goals Growth Histone H3 Histones Human Human Cell Line In Vitro Individual Knowledge Lead Life Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Mesenchymal Mission Modeling Molecular Multienzyme Complexes Mus Mutation National Cancer Institute Notch Signaling Pathway Oncoproteins Operative Surgical Procedures Outcome Outcomes Research Pathogenesis Pathway interactions Patients Pharmacology Polycomb Prevention Primary Neoplasm Public Health Radiation therapy Research Research Support Sampling Signal Pathway Signal Transduction Signaling Molecule Specimen Testing Therapeutic Time Xenograft procedure activin A angiogenesis base cancer therapy cell growth cell motility combat driver mutation effective therapy efficacious treatment gain of function human model in vivo inhibitor/antagonist innovation mouse model mutant notch protein novel palliative preclinical trial prevent receptor reduce symptoms self-renewal therapeutically effective tool transcription factor tumor tumorigenesis

项目摘要

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Recently, novel mutations in ACVR1, a BMP pathway receptor, were discovered that commonly co-occur with a K27M mutation in the gene encoding histone H3.1 (H3.1 K27M) in DIPG patient samples. The overall objectives of this proposal are to identify the mechanisms by which mutant ACVR1 and H3.1 K27M contribute to DIPG pathogenesis and to uncover strategies to pharmacologically target these mutations or downstream signaling molecules. Our central hypothesis is that mutant ACVR1 and H3.1 K27M contribute to brainstem gliomagenesis by activating the Stat3 and Notch signaling pathways, respectively. We plan to use novel genetically engineered mouse models representing primary tumors growing in their native microenvironment to interrogate the effects of both mutant ACVR1 and H3.1 K27M on gliomagenesis, proliferation, apoptosis, cell differentiation, self- renewal, cell motility, and angiogenesis in vitro and in vivo. We will also use both genetic and pharmacologic tools to determine the contributions of Stat3 and Notch to ACVR1-mediated functions and to H3.1 K27M-mediated functions, respectively. Finally, we will test a panel of ACVR1, Stat3, and Notch inhibitors in vitro and in vivo in both human and murine DIPG models. Once it is understood how ACVR1 mutations and H3.1 K27M contribute to DIPG pathogenesis, the relevant developmental pathways can be manipulated pharmacologically, resulting in new and innovative therapeutic approaches that are based upon the basic biology inherent, and specific, to DIPG. We anticipate these outcomes will have a positive impact by 1) laying the foundation for future pre-clinical and clinical trials for DIPG, 2) characterizing the first genetically engineered mouse models of DIPG driven by mutant ACVR1 and H3.1 K27M, and 3) advancing our understanding of signaling pathway activities that are essential for DIPG growth.