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.

项目概要该提案的目标是了解中枢和外周细胞改变的机制神经免疫信号串扰与颗粒体蛋白前体导致额颞叶痴呆的神经退行性变突变 (FTD-GRN)、阿尔茨海默病 (AD) 相关痴呆 (ADRD) 和最常见的痴呆 60 岁以下的人群。GRN 突变是显性遗传 FTD 的主要原因之一。 GRN 突变通常会导致 PGRN 单倍体不足，血浆颗粒体蛋白前体水平降低 >50% 相对于对照，PGRN 与多种功能有关，包括炎症和溶酶体。目前尚不清楚神经退行性过程是否仅由功能失调的神经元驱动。大脑驻留的小胶质细胞或外周免疫系统的过度激活是否有助于神经炎症和神经退行性过程已被报道为血脑屏障渗漏。在患有 AD 和 FTD 的患者中，浸润性单核细胞可能在突触修剪和 FTD 中的神经退行性疾病迄今为止一直被忽视，因此，我们的研究将集中于调查 FTD 中的神经退行性变。外周免疫细胞和小胶质细胞之间功能失调的串扰程度及其对神经元的影响在目标 1 中，我们建议：使用基于 iPSC 衍生神经元 (i-N)、小胶质细胞 (i-MG) 和单核细胞/巨噬细胞的 FTD 人类模型 (i-MO/i-MAC) 在 2D 或 3D 培养中，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骨髓细胞功能障碍的机制及其此外，我们将测试几种药物。目前正在针对其他医疗状况进行临床开发，以增加 PGRN 表达并逆转小鼠 FTD-GRN 神经元的神经退行性变能够挽救人类 i- 的疾病表型 MG、i-MO/i-MAC 和 i-N 培养物，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 小鼠模型中进行补充体内研究突变和 PGRN 单倍体不足，我们之前报道过神经变性和溶酶体我们将检验溶酶体浸润外周免疫细胞的假设。在 FTD-GRN 动物模型中，功能障碍会导致神经炎症和神经变性。 3，我们将定义并验证 FTD- 的稳健、保守且功能明确的疾病相关特征相关的小胶质细胞/单核细胞用于系统级比较分析、生物信息驱动分析和未来化学基因组学筛选。