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Role of central and peripheral immune crosstalk in FTD-Grn neurodegeneration

中枢和外周免疫串扰在 FTD-Grn 神经变性中的作用

基本信息

批准号：
10514263
负责人：
STEVEN M FINKBEINER
金额：
$ 244.69万
依托单位：
UNIVERSITY OF FLORIDA
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：
2022-08-17 至 2025-07-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514263
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Autopsy Bioinformatics Biological Assay Blood - brain barrier anatomy Brain Cells Central Nervous System Diseases Chemicals China Coculture Techniques Data Dementia Development Disease Dose Extravasation Frontotemporal Dementia Functional disorder Future Genes Genomics Goals Health Homeostasis Human Human Genetics Imaging technology Immune Immune System Diseases Immune system Immunologic Monitoring Immunophenotyping In Vitro Induced pluripotent stem cell derived neurons Infiltration Inflammation Inflammatory Inherited Mediating Medical Methodology Microglia Modeling Morphology Mus Mutation Myelogenous Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuroimmune Neurons Organoids Outcome PGRN gene Patients Peripheral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phenotype Plasma Play Process Prosencephalon Reporting Role Signal Transduction Stroke System Systems Biology Technology Testing Tissues Transgenic Model base cell type clinical development comparative disease phenotype functional genomics granulin human model in vivo induced pluripotent stem cell innovation loss of function mutation macrophage monocyte mortality risk mouse model multidisciplinary neuroinflammation neuron loss neuropathology novel strategies prognostic robotic microscopy serial imaging synaptic pruning therapy development three dimensional cell culture transcriptomics

项目摘要

PROJECT SUMMARY The goal of this proposal is to understand the mechanisms by which alterations in central and peripheral neuroimmune signaling crosstalk contribute to neurodegeneration in frontotemporal dementia with progranulin mutations (FTD-GRN), an Alzheimer’s Disease (AD)-related dementia (ADRD), and the most common dementia in people younger than 60. GRN mutations are among the leading causes of dominantly inherited FTD. These GRN mutations typically cause PGRN haploinsufficiency, with plasma progranulin levels reduced by >50% relative to controls. PGRN has been implicated in a variety of functions, including inflammation and lysosomal homeostasis. It is unclear whether neurodegenerative processes are driven solely by dysfunctional neurons and brain-resident microglia or whether hyperactivation of the peripheral immune system contributes to neuroinflammatory and neurodegenerative processes. As blood-brain barrier leakage has been reported in patients with AD and FTD, it is possible that infiltrating monocytes play a key role in synaptic pruning and neurodegeneration in FTD that has so far been over-looked. Thus, our studies will focus on investigating the extent of dysfunctional crosstalk between peripheral immune cells and microglia and its effects on neuronal integrity and function in various mouse and human iPSC-derived models of FTD-GRN. In Aim 1, we propose to use human models of FTD based on iPSC-derived neurons (i-N), microglia (i-MG) and monocytes/macrophages (i-MO/i-MAC) in 2D or 3D culture, together with an innovative longitudinal imaging technology, robotic microscopy (RM), to investigate mechanisms of human central and peripheral myeloid cell dysfunction and its associated contribution to neurodegeneration in the context of FTD. In addition, we will test several drugs currently in clinical development for other medical conditions that increase PGRN expression and reverse neurodegeneration of mouse FTD-GRN neurons for their ability to rescue the disease phenotype of human i- MG, i-MO/i-MAC, and i-N cultures, which will support their potential development as treatments for FTD patients. In Aim 2, we will conduct complementary in vivo studies in mouse models of FTD-GRN with the GrnR493X/+ mutation and PGRN haploinsufficiency in which we previously reported neurodegeneration and lysosomal dysfunction in vitro. We will test the hypothesis that infiltration of peripheral immune cells with lysosomal dysfunction contributes to neuroinflammation and neurodegeneration in this animal model of FTD-GRN. In Aim 3, we will define and validate a robust, conserved, and functionally defined disease-associated signature of FTD- associated microglia/monocytes for systems-level comparative analysis, bioinformatic driver analysis, and future chemical genomics screens.

项目总结这项建议的目标是了解中枢和外周的改变所依据的机制神经免疫信号串扰对额颞叶痴呆患者神经退变的影响突变(FTD-GRN)，一种阿尔茨海默病(AD)相关痴呆(ADRD)，以及最常见的痴呆在60岁以下的人群中。GRN突变是主要遗传性FTD的主要原因之一。这些 GRN突变通常会导致PGRN单倍性功能不全，血浆原颗粒水平降低50% 相对于控件。PGRN与多种功能有关，包括炎症和溶酶体动态平衡。目前尚不清楚神经退行性变过程是否仅由功能障碍的神经元和或外周免疫系统的过度激活是否有助于脑内小胶质细胞神经炎性和神经变性过程。据报道，由于血脑屏障渗漏，在AD和FTD患者中，单核细胞的浸润可能在突触修剪和到目前为止，FTD中的神经变性一直被忽视。因此，我们的研究将集中在调查外周免疫细胞与小胶质细胞功能失调的程度及其对神经元的影响在各种小鼠和人类IPSC衍生的FTD-GRN模型中的完整性和功能。在目标1中，我们建议使用基于IPSC来源的神经元(I-N)、小胶质细胞(I-MG)和单核/巨噬细胞的人类FTD模型 (I-MO/I-MAC)在2D或3D文化中，结合创新的纵向成像技术，机器人显微镜(RM)，研究人类中枢和外周髓系细胞功能障碍的机制及其在FTD背景下对神经退行性变的相关贡献。此外，我们还将测试几种药物目前正处于临床开发中，用于其他疾病，增加PGRN的表达和逆转小鼠FTD-GRN神经元的神经变性及其对人I-GRN疾病表型的挽救能力 MG、I-MO/I-MAC和I-N培养，这将支持它们作为FTD患者治疗的潜在发展。在目标2中，我们将使用GrnR493X/+在FTD-GRN小鼠模型上进行补充体内研究突变和PGRN单倍体不足，我们先前报道了神经变性和溶酶体体外功能障碍。我们将验证溶酶体对外周免疫细胞渗透的假设在这种FTD-GRN动物模型中，功能障碍导致神经炎症和神经变性。在AIM 3，我们将定义和验证FTD的稳健、保守和功能定义的疾病相关签名- 相关的小胶质细胞/单核细胞用于系统水平的比较分析、生物信息学驱动因素分析和未来化学基因组学筛选。