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Pericyte-neuronal crosstalk in health and Alzheimer's Disease

健康和阿尔茨海默病中的周细胞-神经元串扰

基本信息

批准号：
10551225
负责人：
Zhen Zhao
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551225
关键词：
3-Dimensional Ablation Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Animal Model Basement membrane Behavior Behavioral Blood - brain barrier anatomy Blood Vessels Blood flow Brain Cells Central Nervous System Diseases Coculture Techniques Communication Complex Data Defect Dementia Development Developmental Process Disease Endothelial Cells Event Exhibits Functional disorder Gene Expression Goals Growth Growth Factor Guidelines Health Hippocampus Histologic Human IGF2R gene Impairment In Vitro Injury Insulin Signaling Pathway Insulin-Like Growth Factor II Insulin-Like-Growth Factor I Receptor Investigation Knockout Mice Knowledge Learning Mediating Memory Memory impairment Metabolic Metabolic Diseases Modeling Molecular Mus Mutation Nervous System Neurodegenerative Disorders Neuronal Dysfunction Neurons Outcome PIK3CG gene Paracrine Communication Pathogenesis Pathologic Pathology Pathway interactions Peptides Pericytes Phosphotransferases Play Reproducibility Role Signal Pathway Signal Transduction Stroke System Testing Therapeutic Toxic effect Transgenic Model Vascular System amyloid pathology behavior test brain abnormalities brain dysfunction brain health cerebrovascular conditional knockout data mining genetic manipulation glycogen synthase kinase 3 beta hyperphosphorylated tau in vivo information processing insight mouse model nerve stem cell nervous system disorder neurodevelopment neurogenesis neuroinflammation neuron development neurotrophic factor neurovascular neurovascular unit novel novel therapeutics paracrine peptide hormone receptor-mediated signaling single-cell RNA sequencing synaptogenesis tau Proteins tau-1 three dimensional cell culture tissue oxygenation

项目摘要

SUMMARY Neuronal functions and brain connectivity require a highly coordinated neurovascular unit (NVU). Neurons and vascular cells are not just adjacently located; they communicate with each other vigorously via different signaling modules. Pericytes are vascular mural cells of the endothelium and vital integrators of NVU functions, including maintaining the blood-brain barrier (BBB) and vascular integrity, regulating blood flow and tissue oxygenation, modulating neuroinflammation and supporting neuronal health. Pericyte injury and loss occur commonly in CNS diseases including Alzheimer’s disease and dementia. Our current knowledge implicates a critical role of pericytes for neuronal functions, which calls for a thorough investigation of pericyte–neuronal communication for different neuronal functions in health and particularly in Alzheimer’s disease. Using new 3D co-culture systems and novel transgenic models, we found that pericytes can directly regulate neurogenesis and neuronal functions, which can be attributed to pericyte-derived insulin-like growth factor 2. IGF2 is a peptide hormone with multiple roles in regulating metabolic functions and developmental processes. Human with IGF2 mutation and mice lacking IGF2 exhibited strong growth defects with abnormal neural development. IGF2 is produced locally in the brain; however, the roles of brain IGF2 in neurogenesis and neuronal dysfunction in CNS diseases are poorly understood. Our preliminary studies additionally indicated that IGF2 mediates pericyte-neuronal communication by activating a noncanonical IGF2R-Gαi-PLC pathway to enhance neuronal functions, as well as stimulating a canonical PI3K/Akt pathway to promote neurogenesis or suppressing Tau-phosphorylation. Here, we propose to study the functional crosstalk between pericytes and neurons, and examine the influence of IGF2-mediated paracrine signaling on neurogenesis during development (AIM1), on neuronal maturation and functions in adult (AIM2), and on AD-like pathogenesis (AIM3). Follow the Rigor and Reproducibility guidelines, we plan to: i) explore pericyte–neuronal crosstalk using 3D co-culture systems; ii) pinpoint the receptor mediated signaling by manipulating gene expressions and key kinase activities; iii) to determine the role of pericyte-specific IGF2 on neurogenesis and neuronal functions in new pericyte ablation and Igf2 conditional knockout mouse models; iv) examine the role of IGF2- mediated pericyte–neuronal crosstalk during AD-like pathogenies in mice using complex behavioral tests and histological analysis. We hope to generate first evidence of functional pericyte-neuron crosstalk for brain function in health and diseases, and pinpoint the mechanism of this signaling at molecular level for IGF2-mediated pericyte-neuron crosstalk. The outcomes may provide new insights to the IGF system and neurovascular interaction in brain, and close an important gap between metabolic diseases and CNS neurodegenerative diseases such as AD.

概括神经元功能和大脑连接需要高度协调的神经血管单元（NVU）。神经元和血管细胞不仅相邻；他们通过不同的方式积极沟通信号模块。周细胞是内皮的血管壁细胞和 NVU 功能的重要整合者，包括维持血脑屏障 (BBB) 和血管完整性、调节血流和组织氧合、调节神经炎症和支持神经元健康。发生周细胞损伤和丢失常见于中枢神经系统疾病，包括阿尔茨海默病和痴呆症。我们目前的知识表明周细胞对神经元功能的关键作用，这需要对周细胞-神经元的彻底研究健康中，特别是阿尔茨海默病中不同神经元功能的沟通。使用新的3D共培养系统和新颖的转基因模型，我们发现周细胞可以直接调节神经发生和神经元功能，这可归因于周细胞衍生的胰岛素样生长因子 2。 IGF2是一种肽激素，在调节代谢功能和发育过程中具有多种作用。具有 IGF2 突变的人类和缺乏 IGF2 的小鼠表现出强烈的生长缺陷和神经异常发展。 IGF2 在大脑局部产生；然而，大脑 IGF2 在神经发生中的作用和中枢神经系统疾病中的神经元功能障碍尚不清楚。我们的初步研究还表明 IGF2 通过激活非经典 IGF2R-Gαi-PLC 通路来介导周细胞-神经元通讯增强神经元功能，以及刺激经典 PI3K/Akt 通路以促进神经发生或抑制 Tau 磷酸化。在这里，我们建议研究周细胞和神经元，并检查 IGF2 介导的旁分泌信号对神经发生的影响发育 (AIM1)、成人神经元成熟和功能 (AIM2) 以及 AD 样发病机制（目标3）。遵循严谨性和可重复性指南，我们计划： i) 探索周细胞-神经元串扰使用 3D 共培养系统； ii) 通过操纵基因表达来查明受体介导的信号传导和关键激酶活性； iii) 确定周细胞特异性 IGF2 对神经发生和神经元的作用在新的周细胞消融和 Igf2 条件敲除小鼠模型中发挥作用； iv) 检查 IGF2-的作用使用复杂的行为测试和小鼠 AD 样致病过程中介导的周细胞-神经元串扰组织学分析。我们希望获得功能性周细胞-神经元串扰对健康和大脑功能的第一个证据。疾病，并在分子水平上查明 IGF2 介导的周细胞神经元的信号传导机制相声。研究结果可能为大脑中 IGF 系统和神经血管相互作用提供新的见解，缩小代谢疾病与 AD 等 CNS 神经退行性疾病之间的重要差距。