Deciphering the role of Microglia in Glioblastoma

破译小胶质细胞在胶质母细胞瘤中的作用

基本信息

批准号：
10584233
负责人：
JOSEPH EL EL-KHOURY
金额：
$ 46.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584233
关键词：
3-Dimensional Activities of Daily Living Animals Antibodies Apolipoprotein E Binding Bioinformatics Biology Brain Cells Cessation of life Chemotherapy and/or radiation Coculture Techniques Data Set Diagnosis E protein Excision Genes Genetic Engineering Genetic Transcription Glioblastoma Growth Human Immune Immune system Immunoglobulins In Vitro Infiltration Knockout Mice Lectin Longevity Malignant - descriptor Malignant neoplasm of brain Manuals Measures Microglia Modeling Mus Pathway interactions Patients Peptides Phagocytosis Process Radiation therapy Recombinants Research Role Sialic Acids Testing Time Transcript antimicrobial peptide brain cell cell killing chemotherapy epidermal growth factor receptor VIII experimental study in vivo induced pluripotent stem cell mouse model neoplastic cell neutralizing antibody new therapeutic target pre-clinical sialic acid binding Ig-like lectin standard of care targeted treatment therapeutic target therapeutically effective transcriptome transcriptome sequencing tumor tumor growth

项目摘要

Glioblastomas are the most common primary malignant brain tumors. Total neurosurgical resection of glioblastomas is not possible, and tumors invariably recur even following resection, chemotherapy and radiotherapy. Despite extensive research into the biology of glioblastomas, there has been no change in the standard of care for ~20 years and the median lifespan from time of diagnosis to death remains dismal at ~15 months. This highlights the need for identifying new targets for therapy of these devastating tumors. Glioblastomas are characterized by extensive infiltration of microglia; the main resident innate immune cells of the brain. Yet, despite their large presence, microglia fail to keep the tumor in check and appear to promote tumor growth. The exact mechanism(s) of this pro-tumor role of microglia remain incompletely understood. Using an approach that allows us to selectively identify and isolate microglia present within the tumor (vs. those in the same brain but outside the tumor), we determined the transcriptomes of these Glioblastoma Associated Microglia (GAMi) by RNASeq in a murine model of glioblastoma. We found that glioblastomas reprogram microglial transcriptional networks by downregulating pathways potentially involved in recognizing and killing tumor cells. Specifically, we found that GAMi have downregulated: (a) genes potentially involved in immune sensing and phagocytosis of glioblastoma cells and (b) transcripts potentially involved in direct tumor killing. We also found that most of the changes observed in GAMi may be driven by a microglia specific pathway. We obtained similar findings when we analyzed datasets from human glioblastoma patients. In this application, we propose to test which of these microglial transcriptional changes are functionally important in regulating tumor growth using three preclinical mouse glioblastoma models and a co-culture model of patient-derived human glioblastoma and iPSC-derived microglia. We will also identify the precise microglial pathway(s) that regulates these processes. To achieve this, we propose three specific aims. In aim 1, we will determine if GAMi have reduced functional capacity to recognize and phagocytose tumor cells, and the effect of such reduced capacity on tumor growth. In aim 2, we will determine if GAMi have reduced functional capacity to kill tumor cells, and the effect of such reduced capacity on tumor growth. In aim 3, we determine the specific microglial pathway that regulates microglial sensing and phagocytosis of glioblastoma cells, direct killing of tumor cells and whether targeting such pathway will regulate overall tumor growth. Our studies would provide proof of concept that these pathways can be used as potential effective targets for therapy of this devastating tumor.

胶质母细胞瘤是最常见的原发性恶性脑肿瘤。总神经外科切除胶质母细胞瘤是不可能的，即使在切除，化学疗法和放疗。尽管对胶质母细胞瘤的生物学进行了广泛的研究，但尚未改变〜20年的护理标准和从诊断时间到死亡时间的中位寿命在〜15仍然很沮丧月份。这凸显了确定对这些毁灭性肿瘤治疗的新目标的必要性。胶质母细胞瘤的特征是小胶质细胞广泛浸润。主要的居民先天免疫大脑细胞。然而，尽管存在很大的存在，但小胶质细胞未能控制肿瘤，似乎促进肿瘤生长。小胶质细胞的这种亲肿瘤作用的确切机制仍然不完全理解。使用一种方法使我们能够选择性地识别和隔离小胶质细胞肿瘤（vs.在同一大脑中但在肿瘤之外），我们确定了这些转录组胶质母细胞瘤相关的小胶质细胞（GAMI）在胶质母细胞瘤的鼠模型中。我们发现通过下调潜在参与的途径，胶质母细胞瘤重编程小胶质细胞转录网络识别和杀死肿瘤细胞。具体而言，我们发现Gami已下调：（a）潜在的基因参与胶质母细胞瘤细胞的免疫传感和吞噬作用，以及（b）可能参与的转录本直接杀死肿瘤。我们还发现，在GAMI中观察到的大多数变化可能是由小胶质细胞驱动的特定途径。当我们分析来自人类胶质母细胞瘤患者的数据集时，我们获得了类似的发现。在此应用程序中，我们建议测试这些小胶质细胞转录的哪个更改在功能上是对于使用三个临床前小鼠胶质母细胞瘤模型和共培养模型来调节肿瘤生长的重要重要性由患者衍生的人胶质母细胞瘤和IPSC衍生的小胶质细胞的组成。我们还将确定精确的小胶质细胞调节这些过程的途径。为了实现这一目标，我们提出了三个具体目标。在AIM 1中，我们将确定GAMI是否降低了识别和吞噬细胞肿瘤细胞的功能能力，以及这种减少了肿瘤生长的能力。在AIM 2中，我们将确定GAMI是否降低了功能能力杀死肿瘤细胞，以及能力降低对肿瘤生长的影响。在AIM 3中，我们确定具体调节胶质母细胞瘤细胞的小胶质细胞传感和吞噬作用的小胶质细胞途径，肿瘤直接杀死细胞以及靶向这种途径是否会调节整体肿瘤生长。我们的研究将提供证明这些途径可以用作治疗这种毁灭性肿瘤的潜在有效靶标。