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

• 批准号: 10663066
• 负责人: PEARL A SUTTER
• 金额: $ 4.38万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 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/10663066
• 关键词: 5 year old; Adaptive Immune System; Affect; Age; Anatomy; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Attention; Axon; Behavioral; Brain; Brain Diseases; Brain Injuries; CD8-Positive T-Lymphocytes; CD8B1 gene; Career Choice; Cd68; Cell physiology; Cells; Central Nervous System; Cessation of life; Characteristics; Child; Clinical; Cognitive deficits; Complex; Cytometry; Data; Dedications; 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; 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 infiltration; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Thinking; Time; Tissues; Training; Translating; Transmission Electron Microscopy; adaptive immune response; behavior test; brain tissue; cell type; central nervous system demyelinating disorder; comparison control; 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; spatial relationship; success

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 球形细胞白细胞营养不良（GLD）是一种脱髓鞘的中枢神经系统（CNS）疾病，导致 5岁之前的99％的儿童死亡。 GLD中半乳糖脑苷酶功能突变的丧失 导致脂质心理的有毒积累，目前认为这是基于此发展的基础 疾病。 GLD中存在的行为和认知缺陷的快速发展对于两名患者来说都是毁灭性的 家庭，当前的治疗方法在调节这些症状方面取得了有限的成功。因此，是 对于进一步了解与该疾病的病理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。我们的实验室最近确定了CD8+ T细胞中的新作用 GLD的病理，但是这些CD8+ T细胞募集和激活的基础机制 是未知的。众所周知，小胶质细胞增多是GLD神经病理学和我们的初步数据的重要特征 表明活化的CD68+小胶质细胞在解剖学上用CD8+ T细胞聚集在脱髓鞘病变中 gld。我们还发现，小胶质细胞上调了主要的组织相容性复合物I类（MHC I） Psychosine。这些发现一起表明小胶质细胞是一种合理的抗原呈现细胞类型 在GLD中有助于CD8+ T细胞激活和神经病理学。我们假设小胶质MHC I 表达在GLD中有助于CD8+ T细胞激活。因此，在此提案中，我们将定义和测试 小胶质细胞MHC I在GLD神经病理学和CD8+ T细胞激活中的作用。在AIM 1中，我们将定义 在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 疾病的时间过程。我们还将使用成像质量细胞仪使用人类来证实这些发现 GLD Neurospecimens可以翻译我们的发现。在AIM 2中，我们将确定小胶质MHC I功能的作用 使用小胶质细胞特异性MHC I敲除Twitcher小鼠中神经病理学和CD8+ T细胞反应 GLD小鼠模型中的小鼠研究对疾病病程，神经病理学和CD8+ T细胞的影响 回答。我们还将在功能上检查Psychosine指导小胶质MHC I抗原的能力 表现和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表现。该项目的预期影响可能是我们的转变 思考这种不可治疗疾病的脱髓鞘性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 临床和专业目标是针对我作为医师科学家的未来的。实现这些目标，这是高度的 翻译项​​目将利用强大的智力环境和独特的机会 在UConn医学院和赞助商实验室。总的来说，该提案的预期结果将 培养和支持我在神经和免疫互动中接受培训的职业愿望 为神经疾病的领域做出贡献。