Cell type-specific complement activation and glial reactivity in male and female mice with dietary obesity

饮食性肥胖雄性和雌性小鼠的细胞类型特异性补体激活和神经胶质反应性

• 批准号: 10754112
• 负责人: Alexis M. Stranahan
• 金额: $ 39.42万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-24 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754112
• 关键词: Abbreviations; Address; Adult; Anatomy; Astrocytes; Attenuated; Autologous; Behavioral; Brain; Brain region; Bystander Effect; Cell Death; Cells; Chimeric Proteins; Chronic; Clinical Research; Cognitive deficits; Complement; Complement 3b; Complement 3d Receptors; Complement Activation; Complement Inactivators; Complement Receptor; Data; Dementia; Detection; Development; Diet; Discrimination; Electrophysiology (science); Estrus; Exhibits; Experimental Models; Female; Flow Cytometry; Functional disorder; Gene Expression; Harvest; Heterogeneity; High Fat Diet; Hippocampus; Home; Homeostasis; Hydrogels; Impaired cognition; Implant; Inflammation; Inflammatory; Knowledge; Lectin; Link; Machine Learning; Maps; Measures; Mediating; Metabolic; Methodology; Microfluidics; Microglia; Modeling; Morphology; Mus; Natural Immunity; Nervous System; Neuroglia; Neuroimmune; Neuronal Plasticity; Neurons; Obesity; Overnutrition; Pathogenesis; Pathology; Pathway interactions; Pattern; Peripheral; Pilot Projects; Population; Predisposition; Process; Recombinant Fusion Proteins; Regulation; Research; Resistance; Role; Sex Differences; Signal Transduction; Site; Specificity; Synapses; System; Tamoxifen; Testing; Tissues; Transgenes; Transgenic Mice; Up-Regulation; Women' s Group; Work; Y protein; arm; behavior test; brain cell; brain parenchyma; cell type; dietary; dimorphism; experimental study; functional outcomes; gene induction; glial activation; high throughput analysis; inhibitor; insight; knock-down; male; neuroinflammation; neuropathology; obesogenic; prevent; promoter; reconstruction; recruit; response; sexual dimorphism; sexual role; synaptic function

PROJECT SUMMARY Neuroinflammation is a shared feature of obesity and dementia, but the processes that initiate and perpetuate glial reactivity are not well understood,. Several recent studies, including from our lab, have outlined signaling cascades linking peripheral and central inflammation in obesity in males, but vulnerability to obesity-induced metabolic pathology is sexually dimorphic, and susceptibility to neuroinflammation follows similar patterns. Adult females exhibit stronger innate immunity, and evidence from clinical and experimental studies suggests that this dimorphism involves sex differences in activation of complement. However, current understanding of tissue- specific complement activation remains rudimentary due to the scarcity of approaches for cell type-specific manipulation. To this end, we generated transgenic mice with inducible, cell type-specific deletion of the endogenous complement inhibitor Crry, and will use this model to distinguish between target cells and 'bystander' populations in the adult brain. After determining whether selective activation of complement is sufficient for neuroinflammation, we will examine the role of sexually dimorphic complement activation as a mechanism for differential vulnerability to synaptic and behavioral dysfunction on obesogenic diets. These themes will be addressed using state-of-the-art methodology, including newly developed strategies for high-throughput morphometric analysis of glial cells in cleared brains and region-specific manipulation of glial gene expression.

项目概要 神经炎症是肥胖和痴呆症的共同特征，但引发和持续的过程 神经胶质反应性尚不清楚。最近的几项研究，包括我们实验室的研究，概述了信号传导 与男性肥胖的外周和中枢炎症相关的级联反应，但易受肥胖引起的影响 代谢病理学具有性别二态性，并且对神经炎症的易感性遵循相似的模式。成人 女性表现出更强的先天免疫力，临床和实验研究的证据表明，这 二态性涉及补体激活的性别差异。然而，目前对组织的了解 由于缺乏细胞类型特异性的方法，特异性补体激活仍然处于初级阶段 操纵。为此，我们培育了具有可诱导的、细胞类型特异性缺失的转基因小鼠 内源性补体抑制剂 Crry，并将使用该模型来区分靶细胞和“旁观者” 成人大脑中的人群。在确定选择性激活补体是否足以 神经炎症，我们将研究性二态性补体激活作为一种机制的作用 致肥胖饮食对突触和行为功能障碍的不同脆弱性。这些主题将是 使用最先进的方法来解决，包括新开发的高通量策略 透明大脑中神经胶质细胞的形态分析和神经胶质基因表达的区域特异性操作。