Elucidating the role of CHI3L1/YKL-40 in Alzheimer's disease

阐明 CHI3L1/YKL-40 在阿尔茨海默病中的作用

基本信息

批准号：
10901027
负责人：
Yu-Wen Alvin Huang
金额：
$ 38.57万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901027
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker Amyloidosis Anti-Inflammatory Agents Astrocytes Binding Biological Biological Assay Biological Models Biology Brain CHI3L1 gene Cell Surface Receptors Chitinase Clinical Collaborations Complex Data Development Disease Elements Feedback Funding Gliosis Goals Health Human Immune response In Vitro Induction of Apoptosis Inflammatory Inflammatory Response Knowledge Laboratories Lentivirus Macrophage Mediating Methodology Methods Microglia Mission Mutation NF-kappa B Natural Immunity Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neurons Neurophysiology - biologic function Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Peripheral Phenotype Process Property Proteins Public Health Publishing Reagent Receptor Signaling Research Research Personnel Role Signal Induction Signal Pathway Signal Transduction Signaling Molecule Stress System Testing Therapeutic Tissues United States National Institutes of Health Universities Work brain cell cell type disability early detection biomarkers glial activation human stem cells improved induced pluripotent stem cell inflammatory modulation inhibitor injury and repair mutant neural neuroinflammation neuroprotection neurotoxic neurotoxicity presenilin-1 prevent receptor receptor binding receptor for advanced glycation endproducts response stem cell model therapy development translational potential translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Chitinase-3-like protein 1 (CHI3L1/YKL-40) is well known as a powerful biomarker for early detection of neuroinflammation and Alzheimer’s disease (AD). While in peripheral tissues CHI3L1 has been well characterized to regulate a wide range of immune and inflammatory responses, how it acts in the brain in the process of neuroinflammation and AD development remains largely unknown. Recent evidence shows that CHI3L1 is primarily secreted by activated astrocytes to signal a neurotoxic inflammatory response across major brain cell types. The dynamic interactions between microglia, astrocytes and neurons are among the major drivers for the inflammatory neurotoxicity underlying development of AD pathology. Disentangling such intricate cellular cross-talk in human neural systems, and the role of CHI3L1 in this process, thus signifies a critical need for developing therapeutics for AD and relevant neurodegenerative disorders. The long-term goal of my laboratory is to understand the pathogenic determinants of neurodegeneration to inform treatments for AD. Using human stem cell-based methodologies, the overall objectives in this application are: i) to define the signaling mechanism whereby CHI3L1 governs glial activation and neurodegeneration; and ii) to develop the translational potential of these signaling mechanisms to prevent neuronal damage in AD. Supported by our preliminary data, our central hypothesis is that astrocyte-derived CHI3L1 functions as a signaling molecule to mediate inflammatory responses in a cell type-specific manner – promoting neuronal degeneration and regulating microglial inflammatory profiles. We also hypothesize that silencing neuronal CHI3L1 signaling will dampen neurotoxicity and ameliorate AD pathogenesis. We propose to exploit iPSC-based pure and mixed human neural cultures (microglia, astrocytes and neurons) to anatomize the inter-cellular interactions and rigorously test our hypotheses. Three specific aims will be pursued to attain the overall objectives: in Aim 1, we will identify the neuronal CHI3L1 receptor and downstream signaling pathway that convey the detrimental effects of CHI3L1 on neurodegeneration in AD, using human neuronal cultures derived from isogenic control and multiple AD mutant iPSC lines (from NIH-funded iNDI); in Aim 2, we will define the CHI3L1-modulated inflammatory properties of microglia in AD, by control and AD mutant iPSC-derived human microglia; in Aim 3, we will decide the mechanism of CHI3L1 function in astrocyte-microglial interactions for neurodegeneration in AD, aided by a reductionist method to dissect the neuroprotective element out of the neuron-glial and glia-glial interactions of neuroinflammation - the tricultures of human microglia, astrocytes and neurons generated from control and AD mutant iPSCs. Our expected outcomes are to define an essential CHI3L1 signaling mechanism governing neuroinflammation underlying AD neurodegeneration. This work will elucidate the biology of a prominent AD biomarker, which will define a new path for AD/ADRD treatment and thus constitutes a significant positive impact.

项目摘要/摘要几丁质酶-3样蛋白1（CHI3L1/YKL-40）众所周知是一种强大的生物标志物，用于早期检测神经炎症和阿尔茨海默氏病（AD）。而在外围组织中，chi3l1很好特征是调节广泛的免疫和炎症反应，其在大脑中的作用神经炎症和AD发育的过程在很大程度上仍然未知。最近的证据表明 CHI3L1主要由活化的星形胶质细胞分泌，以在主要的脑细胞类型。小胶质细胞，星形胶质细胞和神经元之间的动态相互作用是主要的 AD病理发展的炎症性神经毒性的驱动因素。解开这种复杂的人类神经元系统中的细胞串扰，以及Chi3L1在此过程中的作用，即表示关键需求用于开发用于AD和相关神经退行性疾病的治疗。我的长期目标实验室将了解神经退行性的致病决定剂，以告知AD治疗方法。使用基于人类干细胞的方法，此应用程序中的总体目标是：i）定义信号 CHI3L1控制神经胶质激活和神经退行性的机制； ii）开发翻译这些信号传导机制的潜力，以防止AD中的神经元损伤。在我们的初步数据的支持下我们的中心假设是星形胶质细胞衍生的CHI3L1充当介导的信号分子细胞类型特异性的炎症反应 - 促进神经元变性和调节小胶质细胞炎症特征。我们还假设沉默的神经元CHI3L1信号将Dancen 神经毒性和改善AD发病机理。我们建议利用基于IPSC的纯和混合人类神经元培养物（小胶质细胞，星形胶质细胞和神经元），以解剖细胞间相互作用并严格测试我们的假设。将追求三个具体目标以实现总体目标：在AIM 1中，我们将确定神经元CHI3L1受体和下游信号通路传达CHI3L1对检测器的影响 AD中的神经变性，使用源自同源性对照和多个AD突变体的人类神经元培养物 IPSC线（来自NIH资助的Indi）；在AIM 2中，我们将定义CHI3L1调节的炎症特性 AD中的小胶质细胞，通过对照和AD突变体IPSC衍生的人类小胶质细胞；在AIM 3中，我们将决定机制 Chi3L1在AD中神经退行性的星形胶质细胞 - 神经相互作用中的CHI3L1功能，由还原论者提供帮助从神经保护元件中剖析神经保护元件的方法神经炎症 - 由对照和AD产生的人类小胶质细胞，星形胶质细胞和神经元的三元文化突变的IPSC。我们的预期结果是定义基本的CHI3L1信号传导机制神经炎症基础AD神经变性。这项工作将阐明著名广告的生物学生物标志物将定义AD/ADRD处理的新途径，因此构成了显着的积极影响。