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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' 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

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)被认为是一种强有力的早期检测几丁质酶的生物标志物 神经炎和阿尔茨海默病(AD)。而在外周组织中，CHI3L1表现良好 以调节广泛的免疫和炎症反应为特征，它如何在大脑中起作用 神经炎症和AD的发展过程在很大程度上仍不清楚。最近的证据表明， CHI3L1主要由激活的星形胶质细胞分泌，发出神经毒性炎症反应的信号 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病理发展潜在的炎性神经毒性的驱动因素。解开如此错综复杂的 人类神经系统中的细胞串扰，以及CHI3L1在这一过程中的作用，因此意味着迫切需要 开发治疗阿尔茨海默病和相关神经退行性疾病的药物。我的长期目标是 实验室是为了了解神经退行性变的致病决定因素，为AD的治疗提供信息。vbl.使用 基于人类干细胞的方法学，本申请的总体目标是：i)定义信号 CHI3L1调控神经胶质细胞活化和神经退行性变的机制；以及ii)发展翻译的 这些信号机制在预防阿尔茨海默病神经元损伤方面的潜力。在我们初步数据的支持下， 我们的中心假设是星形胶质细胞来源的CHI3L1起信号分子的作用 特定细胞类型的炎症反应--促进神经元变性和调节 小胶质细胞炎症特征。我们还假设，沉默神经元CHI3L1信号将抑制 神经毒性和改善AD的发病机制。我们建议开发基于IPSC的纯人类神经和混合人类神经 培养(小胶质细胞、星形胶质细胞和神经元)以解剖细胞间的相互作用并严格测试我们的 假设。为达致整体目标，我们会推行三个具体目标：在目标1中，我们会确定 神经元型CHI3L1受体及其下游信号通路在CHI3L1致病作用中的作用 使用来自同基因对照和多个AD突变体的人类神经元培养，AD中的神经变性 IPSC系(来自NIH资助的INDI)；在目标2中，我们将定义CHI3L1调节的炎症特性 AD中的小胶质细胞，通过对照组和AD突变体IPSC来源的人小胶质细胞；在目标3中，我们将确定其机制 研究CHI3L1在星形胶质细胞-小胶质细胞相互作用中的作用在AD神经退行性变中的作用 从神经元-胶质细胞和胶质细胞-胶质细胞相互作用中剖析神经保护成分的方法 神经炎症-对照和AD产生的人小胶质细胞、星形胶质细胞和神经元的三种培养 突变的ipscs。我们的预期结果是定义一个基本的CHI3L1信号机制， 阿尔茨海默病神经变性的神经炎症。这项工作将阐明一个著名的AD的生物学 生物标志物，这将为AD/ADRD的治疗定义一条新的途径，从而构成重大的积极影响。