The role of microglia as antigen presenting cells in Globoid Cell Leukodystrophy

小胶质细胞作为抗原呈递细胞在球状细胞脑白质营养不良中的作用

基本信息

批准号：
10537159
负责人：
PEARL A SUTTER
金额：
$ 4.23万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
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：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537159
关键词：
5 year old Adaptive Immune System Affect Age Anatomy Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Attention Axon Behavioral Brain Brain Diseases Brain Injuries CD8-Positive T-Lymphocytes CD8B1 gene Career Choice Cell physiology Cells Cessation of life Characteristics Child Clinical Cognitive deficits Complex Cytometry Data Demyelinations Development Disease Disease Marker Disease Progression Environment Exhibits Exposure to Family Flow Cytometry Fostering Future Genetic Diseases Gliosis Globoid cell leukodystrophy Goals Histocompatibility Histocompatibility Antigens Class I Histologic Human Image Immune Immunohistochemistry Immunologics Individual Infant Inflammation Innate Immune Response Knockout Mice Lesion Lipids Location Longevity Major Histocompatibility Complex Measures Metals Microglia Mus Myelin Nature Neuraxis Neuroglia Neurologic Onset of illness Outcome PTPRC gene Paralysed Pathologic Pathology Patients Pattern Peptides Physicians Play Population Psychosine Research Role Sampling Scientist Severity of illness Symptoms T cell response T-Cell Activation T-Lymphocyte Techniques Testing Thinking Time Tissues Training Translating Transmission Electron Microscopy Tumor-infiltrating immune cells adaptive immune response behavior test brain tissue cell type central nervous system demyelinating disorder galactosylceramidase immunological synapse improved knock-down loss of function mutation medical schools mouse model myelination nervous system disorder neuroimmunology neuroinflammation neuropathology novel recruit single-cell RNA sequencing skills training spatial relationship success

项目摘要

ABSTRACT Globoid Cell Leukodystrophy (GLD) is a demyelinating central nervous system (CNS) disease that results in death in 99% of children before the age of 5 years old. Loss of function mutation in galactocerebrosidase in GLD leads to a toxic build-up of the lipid psychosine, which is currently thought to underlie the development of this disease. The rapid progression of behavioral and cognitive deficits present in GLD is devastating for both patients and families, however current treatments have limited success at modulating these symptoms. Therefore, it is critical to further understand the complex cellular changes associated with the pathology of this disease to develop successful therapies for these patients. Our lab has recently identified a novel role for CD8+ T cells in the pathology of GLD, however the mechanism underlying the recruitment and activation of these CD8+ T-cells is unknown. It is known that microgliosis is a prominent feature of GLD neuropathology and our preliminary data indicate that activated CD68+ microglia are anatomically clustered with CD8+ T-cells in demyelinated lesions in GLD. We also find that microglia upregulate major histocompatibility complex class I (MHC I) when exposed to psychosine. Together, these findings indicate that microglia are a plausible antigen presenting cell type contributing to CD8+ T-cell activation and neuropathology in GLD. We hypothesize that microglial MHC I expression contributes CD8+ T-cell activation in GLD. Accordingly, in this proposal, we will define and test the role of microglial MHC I on GLD neuropathology and CD8+ T-cells activation. In Aim 1, we will define the temporal and anatomical expression patterns of microglial MHC I expression in a GLD mouse model over the time course of disease. We will also use imaging mass cytometry to corroborate these findings using human GLD neurospecimens to translate our findings. In Aim 2, we will determine the role of microglial MHC I function to neuropathology and CD8+ T cell responses in twitcher mice using microglial cell-specific MHC I knockout mice in the GLD mouse model to investigate effects on disease course, neuropathology and CD8+ T-cell responses. We will also functionally examine the capability of psychosine to direct microglial MHC I antigen presentation and CD8+ T-cell activation. The long-term goal of this project is to understand the novel role of microglial antigen presentation in GLD neuropathology. The expected impact of this project may be a shift in our thinking on the nature of demyelination in this untreatable disease and the role of microglia in neuropathology. The training goals of this application will provide both skills and training in neuroimmunology and to enhance clinical, and professional goals directed toward my future as a physician scientist. Toward these goals, this highly translational project will take advantage of a strong intellectual environment and unique opportunities available at UConn School of Medicine and in the sponsor's lab. Collectively, the expected outcomes of this proposal will foster and support my career aspirations to achieve training in neurological and immunological interactions and to contribute to the field of neurological disease.

抽象的球状细胞脑白质营养不良 (GLD) 是一种脱髓鞘中枢神经系统 (CNS) 疾病，可导致 99%的儿童在5岁之前死亡。 GLD 中半乳糖脑苷脂酶功能缺失突变导致脂质精神氨酸的毒性积累，目前认为这是这种疾病发展的基础疾病。 GLD 中行为和认知缺陷的快速进展对这两名患者来说都是毁灭性的然而，目前的治疗方法在调节这些症状方面效果有限。因此，它是进一步了解与这种疾病的病理学相关的复杂细胞变化至关重要为这些患者开发成功的疗法。我们的实验室最近发现了 CD8+ T 细胞在 GLD 的病理学，但这些 CD8+ T 细胞招募和激活的机制未知。众所周知，小胶质细胞增生是 GLD 神经病理学的一个突出特征，我们的初步数据表明在脱髓鞘病变中激活的 CD68+ 小胶质细胞在解剖学上与 CD8+ T 细胞聚集在一起 GLD。我们还发现，当小胶质细胞暴露于精神。总之，这些发现表明小胶质细胞是一种可能的抗原呈递细胞类型有助于 GLD 中 CD8+ T 细胞的激活和神经病理学。我们假设小胶质细胞 MHC I 表达有助于 GLD 中 CD8+ T 细胞的激活。因此，在本提案中，我们将定义并测试小胶质细胞 MHC I 对 GLD 神经病理学和 CD8+ T 细胞激活的作用。在目标 1 中，我们将定义 GLD 小鼠模型中小胶质细胞 MHC I 表达的时间和解剖表达模式病程时间。我们还将使用成像质谱流式细胞术来证实这些发现 GLD 神经样本来转化我们的发现。在目标 2 中，我们将确定小胶质细胞 MHC I 功能的作用使用小胶质细胞特异性 MHC I 敲除对 twitcher 小鼠的神经病理学和 CD8+ T 细胞反应进行研究 GLD 小鼠模型中的小鼠研究对病程、神经病理学和 CD8+ T 细胞的影响回应。我们还将从功能上检查psychosine引导小胶质细胞MHC I抗原的能力呈递和 CD8+ T 细胞激活。该项目的长期目标是了解 GLD 神经病理学中的小胶质细胞抗原呈递。该项目的预期影响可能是我们的转变思考这种无法治愈的疾病中脱髓鞘的本质以及小胶质细胞在神经病理学中的作用。该应用程序的培训目标将提供神经免疫学方面的技能和培训，并增强临床和专业目标指向我作为一名医师科学家的未来。为了实现这些目标，高度转化项目将利用强大的智力环境和独特的机会在康涅狄格大学医学院和赞助商的实验室。总的来说，该提案的预期成果将培养和支持我的职业抱负，以实现神经学和免疫学相互作用方面的培训，以及为神经疾病领域做出贡献。