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.

项目总结/摘要 几丁质酶-3样蛋白1（CHI 3L 1/YKL-40）是众所周知的用于早期检测肿瘤的强有力的生物标志物。 神经炎症和阿尔茨海默病（AD）。而在外周组织中，CHI 3L 1表达良好， 其特点是调节广泛的免疫和炎症反应，它如何在大脑中发挥作用， 神经炎症和AD发展的过程在很大程度上仍然未知。最近的证据表明， CHI 3L 1主要由活化的星形胶质细胞分泌，以在主要的神经毒性炎症反应中发出信号。 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病理学发展背后的炎性神经毒性的驱动因素。解开如此复杂的 因此，人类神经系统中的细胞串扰以及CHI 3L 1在此过程中的作用意味着迫切需要 用于开发AD和相关神经退行性疾病的治疗方法。我的长期目标是 实验室的目的是了解神经退行性变的致病决定因素，为AD的治疗提供信息。使用 在基于人干细胞的方法中，本申请的总体目标是：i）定义 CHI 3L 1控制神经胶质细胞活化和神经变性的机制;和ii）开发翻译的 这些信号传导机制的潜力，以防止神经元损伤的AD。根据我们的初步数据， 我们的中心假设是星形胶质细胞衍生的CHI 3L 1作为信号分子介导 以细胞类型特异性方式的炎症反应-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CHI 3L 1信号传导将抑制 神经毒性和改善AD发病机制。我们建议利用iPSC为基础的纯和混合的人类神经 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，我们会致力达致三个具体目标： 神经元CHI 3L 1受体和下游信号通路，传达CHI 3L 1的有害作用， AD中的神经变性，使用来自同基因对照和多种AD突变体的人神经元培养物 iPSC系（来自NIH资助的iNDI）;在目标2中，我们将定义 通过对照和AD突变体iPSC衍生的人小胶质细胞，我们将在目的3中确定其机制。 CHI 3L 1在AD神经退行性变的星形胶质细胞-小胶质细胞相互作用中的功能， 一种从神经元-神经胶质和神经胶质-神经胶质相互作用中分离神经保护元件的方法， 神经炎症-由对照和AD产生的人小胶质细胞、星形胶质细胞和神经元的培养物 突变的iPSC。我们的预期结果是定义一个重要的CHI 3L 1信号传导机制， AD神经变性的神经炎症。这项工作将阐明生物学的一个突出的广告 生物标志物，这将为AD/ADRD治疗定义一条新的途径，从而构成显著的积极影响。