Targeting extracellular signaling-regulated kinase 5 (ERK5) in brain tumors and their microenvironment

靶向脑肿瘤及其微环境中的细胞外信号调节激酶 5 (ERK5)

• 批准号: 10582634
• 负责人: Sameer Agnihotri
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582634
• 关键词: Address; Adult; Apoptosis; Biological Models; Biology; Blood - brain barrier anatomy; Brain Neoplasms; Cancer Etiology; Cells; Cessation of life; Characteristics; Child; Cre-LoxP; Data; Defect; Development; Diffuse intrinsic pontine glioma; Event; Exhibits; Extracellular Domain; Extracellular Signal Regulated Kinases; Genetic Transcription; Glioma; Gliomagenesis; Growth; Growth Factor; Histone H3; Human; In Vitro; Knowledge; Lead; Long-Term Effects; Lysine; MAP Kinase Gene; MAPK1 gene; MAPK3 gene; Macrophage; Malignant Neoplasms; Methylation; Microglia; Modality; Modeling; Molecular; Mus; Mutation; Neuroglia; Neurosciences; Oncoproteins; Outcome; Paracrine Communication; Pathway interactions; Phosphorylation; Phosphotransferases; Population; Production; Proliferating; Proteins; Publications; Publishing; Radiation; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Signal Transduction; System; Testing; Therapeutic; Transactivation; Tumor Promotion; Variant; Work; Xenograft procedure; attenuation; cancer type; cell growth; childhood cancer mortality; cytokine; derepression; experimental study; extracellular; in vitro Model; in vivo; inhibitor; innovation; knock-down; knowledgebase; neoplastic cell; nerve stem cell; novel; novel therapeutics; oligodendrocyte precursor; patient derived xenograft model; patient population; pediatric patients; pharmacologic; precursor cell; small hairpin RNA; transcriptome sequencing; tumor; tumor microenvironment; tumor progression

Background: High-grade gliomas are among the leading cause of cancer-related death in children, with diffuse intrinsic pontine glioma (DIPG) being a highly lethal subtype. DIPG commonly exhibits a mutation in histone H3, referred to as H3K27M, which leads to gliomagenesis. However, the cell signaling events that promote DIPG growth are not fully understood. We have discovered and recently shown that DIPGs are reliant on extracellular signal-regulated kinase 5 (ERK5) for proliferation and survival. However, several critical knowledge gaps of ERK5 function in DIPG remain. We will use an innovative syngeneic DIPG model in combination with well-established models of DIPG to address several questions in this proposal. Specifically, we hypothesize that ERK5 promotes growth through both glioma intrinsic effects and pro-glioma activities of select glioma associated microglia and macrophages (GAMs). Significance: To support our preliminary data and test our hypothesis we will study the role of ERK5 in three aims. Aim 1: Revealing functions of ERK5 in GAMs and the importance of paracrine signaling with DIPG cells will provide valuable knowledge potentially applicable to the development of new therapeutic modalities. Aim 2: Building a new paradigm by understanding the dynamic characteristics of targeting multiple ERK pathways. Aim 3: ERK5 contains both a transactivation domain and kinase domain unlike all other ERKs. Here we will delineate the functional role of these domains and their contribution to glioma growth. Impact. This project leverages unique in vivo and in vitro model systems to study a highly aggressive brain tumor. Our research will inform molecular mechanisms and translational relevance of ERK5 in brain tumors, and be broadly applicable to other types of cancer and neurosciences.

背景：高级神经胶质瘤是儿童与癌症相关死亡的主要原因之一， 弥漫性内在的庞然神经胶质瘤（DIPG）是高度致命的亚型。 DIPG通常在 组蛋白H3，称为H3K27M，导致神经胶质作用。但是，细胞信号事件 促进DIPG增长尚未完全理解。我们已经发现并最近证明了DIPG是Reliant的 在细胞外信号调节的激酶5（ERK5）上，用于增殖和存活。但是，有几个关键 DIPG中ERK5功能的知识差距仍然存在。我们将在 结合完善的DIPG模型，以解决此提案中的几个问题。具体来说， 我们假设ERK5通过神经胶质瘤的内在作用和促旋律瘤活性促进生长 选择胶质瘤相关的小胶质细胞和巨噬细胞（GAM）。意义：支持我们的初步数据 并检验我们的假设，我们将研究ERK5在三个目标中的作用。目标1：揭示ERK5的功能 GAM和旁分泌信号对DIPG细胞的重要性可能会提供有价值的知识 适用于开发新的治疗方式。目标2：建立一个新的范式 了解靶向多个ERK途径的动态特征。 AIM 3：ERK5都包含一个 与所有其他ERK不同，反式激活结构域和激酶结构域。在这里，我们将描述 这些领域及其对神经胶质瘤生长的贡献。影响。该项目在体内和 体外模型系统研究高度侵略性的脑肿瘤。我们的研究将为分子机制提供信息 ERK5在脑肿瘤中的转化相关性，并广泛适用于其他类型的癌症和 神经科学。